Heterocyclic P2X7 antagonists
11623919 · 2023-04-11
Assignee
Inventors
- Paolo Pevarello (Bresso, IT)
- Mariangela Sodano (Bresso, IT)
- Elda Severi (Bresso, IT)
- Rocco Vitalone (Bresso, IT)
- Russell Thomas (Bresso, IT)
- Valentina Cusano (Bresso, IT)
Cpc classification
C07D413/10
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
A61P1/00
HUMAN NECESSITIES
C07D417/06
CHEMISTRY; METALLURGY
C07D271/07
CHEMISTRY; METALLURGY
C07D413/06
CHEMISTRY; METALLURGY
C07D285/08
CHEMISTRY; METALLURGY
International classification
C07D271/07
CHEMISTRY; METALLURGY
C07D285/08
CHEMISTRY; METALLURGY
C07D413/06
CHEMISTRY; METALLURGY
C07D413/10
CHEMISTRY; METALLURGY
C07D417/06
CHEMISTRY; METALLURGY
Abstract
Disclosed are compounds of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing them, and to a process for the preparation of the compounds: ##STR00001##
R.sup.1 is independently selected from hydrogen atom, amine group, monocyclic or bicyclic aliphatic, aromatic, heteroaliphatic or heteroaromatic ring. R.sup.2 is independently selected from monocyclic or bicylic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring, C.sub.1-C.sub.6 alkyl, alkenyl or alkynyl chain. n is 1 or 2; preferably n is 1. m is 0, 1 or 2; preferably m is 0. R.sup.3 and R.sup.4 can be, independently, —H, —F, C.sub.1-C.sub.4 alkyl, —OH, —OC.sub.1-C.sub.4 alkyl; preferably they are both —H. X is O or S. R.sup.5 is —H or —CH.sub.3 optionally substituted by one or more fluorine atoms; preferably R.sup.5 is hydrogen. The compounds can be used in the treatment of conditions or diseases mediated by P2X7 receptor.
Claims
1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof: ##STR00371## including any stereochemically isomeric form thereof, wherein: R.sup.1 is independently selected from aliphatic, aromatic, heteroaliphatic or heteroaromatic ring selected from cyclopentyl, cyclohexyl, piperidine, morpholine, pyrrolidine, piperazine, phenyl, pyridine, oxazole, pyrazole or thiazole, wherein each of said moieties is unsubstituted or substituted by one or more substituents selected from C.sub.1-C.sub.4 alkyl, unsubstituted or substituted by one or more halogen atom(s), halogen, C.sub.1-C.sub.4 alkoxy or phenyl group unsubstituted or substituted by C.sub.1-C.sub.4 alkyl, or the above reported aliphatic, aromatic, heteroaliphatic or heteroaromatic rings may be condensed with another aromatic, heteroaromatic or heteroaliphatic ring; R.sup.2 is independently selected from monocyclic or bicylic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring, C.sub.1-C.sub.4 alkyloxy, alkenyl or alkynyl chain, unsubstituted or substituted by one or more substituents selected from C.sub.1-C.sub.4 alkyl unsubstituted or substituted by one or more halogen atom(s), halogen, C.sub.1-C.sub.4 alkoxy, cyano, C.sub.1-C.sub.4 alkylthio, SO-C.sub.1-C.sub.4 alkyl, or SO.sub.2-C.sub.1-C.sub.4 alkyl; n is 1; m is 0; R.sup.3 and R.sup.4 are —H; X is 0; R.sup.5 is —H.
2. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein: R.sup.2 is independently selected from phenyl, pyridine, pyrimidine, pyrazole, imidazole, naphthalene, quinoline, thiazole, furan, oxazole, oxadiazole, C.sub.3-C.sub.7 cycloalkyl, pyran, tetrahydropyran, dioxane, C.sub.1-C.sub.4 alkyloxy, aliphatic, aromatic or heteroaromatic bicyclic rings, or C.sub.3-C.sub.5 alkynyl chain, wherein R.sup.2 is unsubstituted or substituted with one or more C.sub.1-C.sub.4 alkyl unsubstituted or substituted by one or more halogen atom(s), halogen or C.sub.1-C.sub.4 alkoxy.
3. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein: R.sup.1 is independently selected from the group consisting of cyclopentyl, cyclohexyl, piperidine, morpholine, pyrrolidine, piperazine, phenyl, pyridine, oxazole, pyrazole or thiazole; wherein R.sup.1 is unsubstituted or substituted with methyl, methoxy, halogen, trifluoromethyl or phenyl group unsubstituted or substituted by methyl; and each of the above reported aliphatic, aromatic or heteroaliphatic or heteroaromatic ring may be condensed with another aromatic or heteroaromatic ring; R.sup.2 is independently selected from phenyl, pyridine, pyrimidine, pyrazole, imidazole, naphthalene, quinoline, thiazole, furan, oxazole, oxadiazole, C3-C7 cycloalkyl, pyran, tetrahydropyran, dioxane, aliphatic bicyclic rings, C.sub.1-C.sub.3 alkyloxy, C.sub.1-C.sub.4 alkyl chain or C.sub.3-C.sub.5 alkynyl chain; wherein each one of the above aliphatic, aromatic and heteroaliphatic ring is unsubstituted or substituted with methyl, methoxy, halogen and/or trifluoromethyl group; n is 1; m is 0; ′R.sup.3 and R.sup.4 are —H; X is 0; R.sup.5 is H.
4. A compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 wherein R.sup.1 is independently selected from 3,3-difluorocyclopenthyl, cyclohexyl, 4,4-difluorocyclohexyl, piperidinyl, 3,3-difluoropiperidinyl, 4,4-difluoropiperidinyl, 4,4-difluoro-2-methylpiperidinyl, 3-(4-methylphenyl)piperidinyl, 4H,5H,6H,7H-thieno[3,2-c]pyridine-5-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 3,4-dihydro-2H-1,4-benzoxazin-4-yl, pyrrolidinyl, 4-phenylpiperazinyl, phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-chloro-3-trifluoromethylphenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-, 3- or 4-pyridine, 2-methylpyridin-3-yl, dimethyl-1,2-oxazol-4-yl, trimethyl-1H-pyrazol-4-yl and 4-methyl-1,3-thiazol-5-yl; R.sup.2 is independently selected from 2-phenylmethyl, 1-phenylethyl, 2-phenylethyl, phenyl, 2-, 3-, 4-fluorophenyl, 2-, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-, 4-trifluoromethylphenyl, 2-, 4-methylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-chloro-3-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-bromo-5-fluorophenyl, 4-fluoro-2-methylphenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridine, 2-methylpyridin-3-yl, 6-trifluoromethylpyridin-3-yl, 2-methyl-6-(trifluoromethyl)pyridin-3-yl, naphthalen-1-yl, quinolin-5-yl, 1,3-thiazol-2-y, 1,3-thiazol-5-yl, 4-methyl-1,3-thiazol-5-yl, 5-methyl-1,2-oxazol-3-yl, 1,2-oxazol-3-yl 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, dimethyl-1,2-oxazol-4-yl, 3-(trifluoromethyl)-1H-pyrazol-1-yl, 1,3-dimethyl-1H-pyrazol-5-yl, 1-methyl-1H-imidazol-2-yl, furan-3-yl, 5-(trifluoromethyl)furan-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 3-methyl-1,2,4-oxadiazol-5-yl, pyrimidin-2-yl, pyrimidin-5-yl, 5-fluoropyrimidin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-3-en-1-yl, cyclohexyl, 1-fluorocyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, 2,2-difluorocyclohexyl, 4,4-diflurocyclohexyl, 4-(trifluoromethyl)cyclohexyl, 4-fluorocyclohexyl, 3,3-diflurocyclopentyl, 6,6-difluorobicyclo[3.1.0] hexan-3-yl, bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.1]heptan-2-yl, 1,4-dioxaspiro[4.5]decan-8-yl, oxan-2-yl, oxan-3-yl, oxan-4-yl, 1,4-dioxane-2-yl, methoxy, ethoxy, propoxy, but-1-ynyl, prop-1-ynyl, piperidin-1-yl, and 4,4-difluoropiperidin-1-yl ; n is 1; m is 0; ′R.sup.3 and R.sup.4 are —H; X is 0; R.sup.5 is —H.
5. A compound of formula (I) according to claim 1 which is: 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2,4-dimethoxyphenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4-fluorophenyl)methyl]-4-[(4-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(3,5-dimethoxyphenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-bromo-5-fluorophenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-benzyl-4-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(3-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4-fluorophenyl)methyl]-4-[(4-methyl-1,3-thiazol-5-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2,4-dichlorophenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(2,3-dichlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(2,4-difluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-4-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(2,4-dichlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one bis[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(2-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(2-chlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-benzyl-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2-chlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[2-(trifluoromethyl)phenyl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-fluoro-2-methylphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(3-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2-methylphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(naphthalen-1-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(quinolin-5-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-methyl-1,3-thiazol-5-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(1,3-oxazol-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(1,3-thiazol-5-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(1,3-thiazol-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(dimethyl-1,2-oxazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(pyrimidin-5-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(pyrimidin-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(1,3-oxazol-5-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(pyridin-3-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(pyridin-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(furan-3-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(5-fluoropyrimidin-2-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(1-methyl-1H-imidazol-2-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2,3-dichlorophenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-4-fluorophenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2,4-difluorophenyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one bis[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(3-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2,3-dichlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-4-fluorophenyl)methyl]-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2,4-difluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(pyridin-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[4-(trifluoromethyl)phenyl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-chlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[5-(trifluoromethyl)furan-2-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-methylphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclobutylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{1,4-dioxaspiro[4.5]decan-8-ylmethyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2,3-dichlorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-4-fluorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2,4-dichlorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-fluorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chlorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-(pyridin-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2,4-difluorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(3-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclopropylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclopentylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-dimethylcyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2-methylcyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-{bicyclo[2.2.1]heptan-2-ylmethyl}-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(oxan-3-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(pent-2-yn-1-yl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-{bicyclo[2.2.1]heptan-1-ylmethyl}-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cycloheptylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(oxan-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(oxan-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(but-2-yn-1-yl)-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(1-fluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2,2-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(1,4-dioxan-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(2,2-dimethylcyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(methoxymethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(ethoxymethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(propoxymethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-(pyridin-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-{[2-(trifluoromethyl)phenyl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(3-fluorophenyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-benzyl-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-[(3-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-(pyridin-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-(pyridin-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(4-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-4-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-4-fluorophenyl)methyl]-4-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(2,3-dichlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-{[2-(trifluoromethyl)phenyl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chlorophenyl)methyl]-4-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(2,4-dichlorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one7 4-(cyclohexylmethyl)-3-[(2,4-difluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(2-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[1-(2-chloro-6-fluorophenyflethyl]-4-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-(pyridin-3-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(3-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-benzyl-4-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(3-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(3,3-difluorocyclopentyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one bis(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-(cyclohexylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-(cyclohexylmethyl)-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-(2-chloro-6-fluorobenzyl)-4-[(3,3-difluorocyclopentyl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-(2-chloro-6-fluorobenzyl)-4-[(3,3-difluorocyclopentyl)methyl]-1,2,4-oxadiazol-5(4H)-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(2-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(3-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(2,4-difluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(4-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2,3-dichlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-{[2-(trifluoromethyl)phenyl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2,4-dichlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(3-methoxyphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-benzyl-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-4-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(2-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-{[4-(trifluoromethyl)phenyl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-{[5-(trifluoromethyl)furan-2-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(5-methyl-1,2-oxazol-3-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chlorophenyl)methyl]-3-[(4,4-difluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(4-fluoro-2-methylphenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-({6,6-difluorobicyclo[3.1.0]hexan-3-yl}methyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-ethyl-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-propyl-4,5-dihydro-1,2,4-oxadiazol-5-one 4-butyl-3-[(2-chloro-6-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(2-methylpropyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-(cyclopent-3-en-1-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-{[4-(trifluoromethyl)cyclohexyl]methyl}-1,2,4-oxadiazol-5(4H)-one 3-[(2-chloro-6-fluorophenyl)methyl]-4-[(4-fluorocyclohexyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(5-fluoropyrimidin-2-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-(1,3-thiazol-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(1,3-oxazol-2-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(1,2-oxazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(4-methyl-1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 3-[(4,4-difluorocyclohexyl)methyl]-4-[(1-methyl-1H-imidazol-2-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(3,3-difluorocyclopentyl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(3,3-difluorocyclopentyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(3,3-difluorocyclopentyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(3,3-difluorocyclopentyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(dimethyl-1,2-oxazol-4-yl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(dimethyl-1,2-oxazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(dimethyl-1,2-oxazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(dimethyl-1,2-oxazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-[(trimethyl-1H-pyrazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(trimethyl-1H-pyrazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(trimethyl-1H-pyrazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(trimethyl-1H-pyrazol-4-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(4,4-difluoropiperidin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluoropiperidin-1-yl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(4,4-difluoropiperidin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(4,4-difluoropiperidin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(3,3-difluoropiperidin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(3,3-difluoropiperidin-1-yl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(4,4-difluoro-2-methylpiperidin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-[(4,4-difluoro-2-methylpiperidin-1-yl)methyl]-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 3-(3,4-dihydro-2H-1,4-benzoxazin-4-ylmethyl)-4-[(4-fluorophenyl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-(3,4-dihydro-2H-1,4-benzoxazin-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-(3,4-dihydro-2H-1,4-benzoxazin-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-(3,4-dihydro-2H-1,4-benzoxazin-4-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-ylmethyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-ylmethyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-ylmethyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-ylmethyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-[(4-phenylpiperazin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(4-phenylpiperazin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(cyclohexylmethyl)-3-[(4-phenylpiperazin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(4-phenylpiperazin-1-yl)methyl]-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-(piperidin-1-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-[(piperidin-1-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-{[3-(4-methylphenyl)piperidin-1-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4-fluorophenyl)methyl]-3-{[3-(4-methylphenyl)piperidin-1-yl]methyl}-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(4,4-difluorocyclohexyl)methyl]-3-(1,2,3,4-tetrahydroisoquinolin-2-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-[(2-chloro-6-fluorophenyl)methyl]-3-(pyrrolidin-1-ylmethyl)-4,5-dihydro-1,2,4-oxadiazol-5-one 4-(4-fluorobenzyl)-3-[(4-methyl-1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 4-(2-chloro-6-fluorobenzyl)-3-[(4-methyl-1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 4-(cyclohexylmethyl)-3-[(4-methyl-1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 4-[(4,4-difluorocyclohexyl)methyl]-3-[(4-methyl-1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one 4-[(3,3-difluorocyclopentyl)methyl]-3-[(4-methyl-1,3-thiazol-5-yl)methyl]-1,2,4-oxadiazol-5(4H)-one.
6. A pharmaceutical composition comprising a compound of Formula (I) according to claim 1 and a pharmaceutically acceptable diluent and/or carrier.
7. A method for treatment of conditions or diseases selected from P2X7 receptor mediated conditions or diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) according to claim 1.
8. The method according to claim 7, wherein the conditions or diseases selected from P2X7 receptor mediated conditions or diseases are neurodegenerative, cognitive or psychiatric disorders, neuropathic pain, chronic pain, inflammatory processes of the muscular-skeletal system, liver fibrosis, gastrointestinal tract disorders, genito-urinary tract disorders, ophthalmic diseases, Chronic Obstructive Pulmonary Disease (COPD), cancer and proliferative diseases.
Description
EXPERIMENTAL PART
(1) The following examples illustrate the present invention. Unless explicitly stated otherwise, all particulars (especially percentages and amounts) relate to the weight.
A Synthesis of the Intermediates
(2) Most substituted nitrile derivatives used, as starting materials, were purchased from chemical providers:
(3) TABLE-US-00002 Structure of nitrile derivatives CAS number
(4) Some nitrile derivatives used, as starting materials, were synthesised according to this general procedure:
(5) K.sub.2CO.sub.3 (1.5 eq) was added to a solution of opportune amine (1.0 eq) and Bromoacetonitrile (1.1 eq) in ACN (10 mL) and the mixture was stirred on at rt. Then, precipitated salts were filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (DCM/AcOEt 1:1 v/v) giving pure nitrile derivatives. (y=61-97%).
(6) Using this procedure, intermediates 0a (y=64%), 0b (y=70%) were prepared starting from the corresponding, commercially available starting materials.
(7) TABLE-US-00003 Intermediate Structure 0a
Preparation of N′-hydroxyethanimidamide Derivatives (IV) (Typical Procedure)
(8) Hydroxylamine hydrochloride (2.5 eq) and K.sub.2CO.sub.3 (2.5 eq) were dissolved in EtOH (20-40 mL) and the mixture was stirred for 30 min at r.t.; then a suitable nitrile derivative (1.0 eq) (V) was added and the reaction mixture was heated at reflux for 12 hrs. The precipitated solid was filtered off and the filtrate was condensed under reduced pressure. The residue was purified by CC (DCM/EtOAc 1:1 v/v) giving the pure N′-hydroxyethanimidamide. (y=35-97%)
(9) Using this procedure, intermediates 1a (y=64%), 1b (y=70%), 1c (y=72%), 1d (y=80%), 1e (y=55%), 1f (y=82%), 1g (y=79%), 1h (y=72%), 1i (y=46%), 1j (y=68%), 1k (y=69%), 1l (y=82%), 1m (y=96%), 1n (y=71%), 1o (y=79%), 1p (y=94%), 1q (y=95%), 1r (y=72%), 1s (y=97%), 1u (y=71%), 1v (y=47%), 1w (y=76%), 1x (y=92%), 1y (y=56%), 1z (y=91%), 1aa (y=76%), 1bb (y=90%), 1cc (y=79%), 1dd (y=72%), 1ee (y=87%), 1ff (y=85%), 1gg (y=61%), 1hh (y=69%), 1ii (y=66%), 1jj (y=88%), 1kk (y=95%), 1ll (y=90%), 1mm (y=84%), were prepared starting from the corresponding, commercially available nitrile derivative.
(10) TABLE-US-00004 Intermediate Structure 1a
Preparation of 1,2,4-oxadiazol-5(4H)-one (II) (Typical Procedure)
(11) To a solution of a suitable intermediate IV (1.0 eq) in 1,4-dioxane (10-30 mL) CDI (1.5 eq) and DBU (1.1 eq) were added at r.t., and the mixture was stirred for 3 hrs at 105° C. After cooling, the mixture was diluted with water, washed with EtOAc, adjusted to pH 2 with 3N HCl and extracted with EtOAc. The EtOAc extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by CC (Hexane/EtOAc 1:1 v/V) yielding the pure 1,2,4-oxadiazol-5(4H)-one. (y=20-98%)
(12) Using this procedure:
(13) intermediate 2a (y=87%) was prepared starting from 1a;
(14) intermediate 2b (y=86%) was prepared starting from 1b;
(15) intermediate 2c (y=85%) was prepared starting from 1c;
(16) intermediate 2d (y=61%) was prepared starting from 1d;
(17) intermediate 2e (y=88%) was prepared starting from 1e;
(18) intermediate 2f (y=59%) was prepared starting from 1f;
(19) intermediate 2g (y=85%) was prepared starting from 1g;
(20) intermediate 2h (y=61%) was prepared starting from 1h;
(21) intermediate 2i (y=41%) was prepared starting from 1i;
(22) intermediate 2j (y=90%) was prepared starting from 1j;
(23) intermediate 2k (y=76%) was prepared starting from 1k;
(24) intermediate 2l (y=77%) was prepared starting from 1l;
(25) intermediate 2m (y=76%) was prepared starting from 1m;
(26) intermediate 2n (y=76%) was prepared starting from 1n;
(27) intermediate 2o (y=61%) was prepared starting from 1o;
(28) intermediate 2p (y=48%) was prepared starting from 1p;
(29) intermediate 2q (y=20%) was prepared starting from 1q;
(30) intermediate 2r (y=46%) was prepared starting from 1r;
(31) intermediate 2s (y=98%) was prepared starting from 1s;
(32) intermediate 2u (y=72%) was prepared starting from 1u;
(33) intermediate 2v (y=72%) was prepared starting from 1v;
(34) intermediate 2w (y=75%) was prepared starting from 1w;
(35) intermediate 2x (y=60%) was prepared starting from 1x;
(36) intermediate 2y (y=40%) was prepared starting from 1y;
(37) intermediate 2z (y=82%) was prepared starting from 1z;
(38) intermediate 2aa (y=86%) was prepared starting from 1aa;
(39) intermediate 2bb (y=89%) was prepared starting from 1bb;
(40) intermediate 2cc (y=67%) was prepared starting from 1cc;
(41) intermediate 2dd (y=44%) was prepared starting from 1dd;
(42) intermediate 2ee (y=52%) was prepared starting from 1ee;
(43) intermediate 2ff (y=84%) was prepared starting from 1ff;
(44) intermediate 2gg (y=61%) was prepared starting from 1gg;
(45) intermediate 2hh (y=56%) was prepared starting from 1hh;
(46) intermediate 2ii (y=83%) was prepared starting from 1ii;
(47) intermediate 2jj (y=40%) was prepared starting from 1jj;
(48) intermediate 2kk (y=57%) was prepared starting from 1kk;
(49) intermediate 2ll (y=57%) was prepared starting from 1ll;
(50) intermediate 2 mm (y=50%) was prepared starting from 1 mm;
(51) TABLE-US-00005 Intermediate Structure 2a
Preparation of 1,2,4-thiadiazol-5(4H)-one (IIa) (Typical Procedure)
(52) A mixture of a suitable intermediate VI (1.0 eq) and TCDI (1.5 eq) in THF (20 mL) was stirred at rt for 30 minutes. The mixture was diluted with water and extracted with EtOAc; the extract was washed with water and dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated in vacuo. The obtained residue was dissolved in THF (20 mL), and Boron trifluoride diethyl etherate (3.0 eq) was added to the solution, and the resulting mixture was stirred at rt for a further 1 hrs. The mixture was diluted with water and extracted with EtOAc; the extract was washed with water and dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated in vacuum. The product was used without purification in the next step. In this way pure 1,2,4-thiadiazol-5(4H)-one was obtained. (y=66-82%)
(53) Using this procedure:
(54) intermediate 3a (y=66%) was prepared starting from intermediate 1g;
(55) intermediate 3b (y=82%) was prepared starting from intermediate 1v;
(56) TABLE-US-00006 Intermediate Structure 3a
(57) General Procedures for the Synthesis of Final Compounds
(58) Method A
Preparation of Examples 1-7
(59) To a solution of intermediate 2 (1.0 eq), a suitable, commercially available alcohol (1.0 eq), and PPh.sub.3 (4.0 eq) in THF (5-10 mL) at 0° C. a DEAD solution 40 wt % in toluene (4.0 eq) was added dropwise; the reaction mixture was stirred at r.t. for 24 hrs under inert atmosphere. The solvent was concentrated under reduced pressure; the residue dissolved in a minimal amount of diethyl ether, and cooled at −20° C. to form a white precipitate (PPh.sub.3O and reduced DEAD) which was filtered off. The filtrate was concentrated under reduced pressure. The crude product was purified by HPLC, giving the pure desired compound. (y=9%-66%)
(60) According to this procedure the following compounds were prepared using the suitable intermediates and alcohols:
(61) TABLE-US-00007 Example Yield Int. Alcohol Ex. 1 60% Int. 2a 2-Chloro-6-fluorobenzyl alcohol (CAS: 56456-50-9). Ex. 2 34% Int. 2a 2,4-Dimethoxybenzyl alcohol (CAS: 7314-44-5). Ex. 3 9% Int. 2a 4-Methoxybenzyl alcohol (CAS: 105-13-5). Ex. 4 66% Int. 2a 3,5-Dimethoxybenzyl alcohol (CAS: 705-76-0). Ex. 5 39% Int. 2a 2-Bromo-5-fluorobenzyl alcohol (CAS: 202865-66-5). Ex. 6 26% Int. 2o 2-Chloro-6-fluorobenzyl alcohol (CAS: 56456-50-9). Ex. 7 16% Int. 2d 2-Chloro-6-fluorobenzyl alcohol (CAS: 56456-50-9).
(62) Method B
Preparation of Examples 8-49
(63) To a cold (0° C.) solution of intermediate 2 (1.0 eq) in MeCN/DMF (5:1 v/v 5-10 mL/1-3 mL) K.sub.2CO.sub.3 (2.5 eq) was added, followed by the suitable commercially available halide (1.2 eq). The reaction was allowed to warm to r.t., and was stirred at same temperature o.n. The reaction was quenched by addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by HPLC giving pure desired compound. (y=14%-83%)
(64) According to this procedure the following compounds were prepared using the suitable intermediates and reactants:
(65) TABLE-US-00008 Ex. Yield Int. Reactant 8 68% 2a 5-(chloromethyl)-4-methyl-1,3-thiazole (CAS: 10014-52-5). 9 50% 2a 2,4-Dichlorobenzyl chloride (CAS: 94-99-5). 10 40% 2a (1-chloroethyl)benzene (CAS: 672-65-1). 11 59% 2a 1-(1-bromoethyl)-4-fluorobenzene (CAS: 65130-46-3). 12 66% 2a (Bromomethyl)cyclohexane (CAS: 2550-36-9). 13 49% 2j 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 14 56% 2n 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 15 56% 2k 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 16 48% 2l 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 17 64% 2m 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 18 70% 2g 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 19 61% 2c 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 20 61% 2f 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2). 21 46% 2g benzyl chloride (CAS: 100-44-7). 22 67% 2g 2-chlorobenzyl chloride (CAS: 611-19-8). 23 37% 2g 2-(trifluoromethyl)benzyl chloride (CAS: 21742-00-7). 24 56% 2g 3-(chloromethyl)-2-methylpyridine (CAS: 120277-68-1). 25 83% 2g (1-chloromethyl)-4-fluoro-2-methylbenzene (CAS: 80141-92-0). 26 73% 2g 3-fluorobenzyl chloride (CAS: 456-42-8). 27 57% 2g 2-methylbenzyl chloride (CAS: 552-45-4). 28 66% 2g 1-(chloromethyl)-2-methoxybenzene (CAS: 7035-02-1). 29 33% 2g 1-(chloromethyl)-naphthalene (CAS: 86-52-2). 30 80% 2g 5-(chloromethyl)quinoline (CAS: 110333-07-8). 31 33% 2g 5-(chloromethyl)-4-methyl-1,3-thiazole (CAS: 10014-52-5). 32 66% 2g 2-Chloromethyl-oxazole (CAS: 185246-17-7). 33 14% 2g 5-(Chloromethyl)thiazole hydrochloride (CAS: 131052-44-3). 34 50% 2g 2-(Chloromethyl)thiazole (CAS: 3364-78-1). 35 30% 2g 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole (CAS: 860807- 20-1). 36 78% 2g 4-(Chloromethyl)-3,5-dimethylisoxazole (CAS: 19788-37-5). 37 35% 2g 5-Chloromethyl-2-(trifluoromethyl)pyridine (CAS: 386715-33-9). 38 21% 2g 5-(Chloromethyl)pyrimidine hydrochloride (CAS: 1337879-54-5). 39 64% 2g 2-(Chloromethyl)pyrimidine hydrochloride (CAS: 936643-80-0). 40 33% 2g 5-(Chloromethyl)oxazole (CAS: 172649-57-9). 41 27% 2g 2-(Chloromethyl)-5-methyl-1,3,4-oxadiazole (CAS: 3914-42-9). 42 28% 2g 3-Picolylchloride hydrochloride (CAS: 6959-48-4). 43 15% 2g 4-(Chloromethyl)pyridine hydrochloride (CAS: 1822-51-1). 44 20% 2g 3-(chloromethyl)-furan (CAS: 14497-29-1). 45 50% 2g 2-(chloromethyl)-5-fluoropyrimidine (CAS: 1196151-61-7). 46 54% 2g 5-(Chloromethyl)-1,3-dimethyl-1H-pyrazole (CAS: 852227-86-2). 47 77% 2g 2-(Chloromethyl)-1-methyl-1H-imidazole (CAS: 19225-92-4). 48 51% 2g 1-(1-bromoethyl)-4-fluorobenzene (CAS: 65130-46-3). 49 40% 2g (1-chloroethyl)benzene (CAS: 672-65-1).
(66) Method C
Preparation of Examples 50-80
(67) To a Cold (0° C.) Solution of Intermediate 2 (1.0 Eq) in MeCN/DMF (5:1 v/v 5-10 mL/1-3 mL) K.sub.2CO.sub.3 was added (1.1 eq), followed by the commercially available halide (0.8 eq). The reaction was allowed to warmed to rt, and then stirred at same temperature for 3 hrs. The reaction was quenched by addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by HPLC giving pure desired compound. (y=12%-97%)
(68) According to this procedure the following compounds were prepared using the suitable intermediates and reactants:
(69) TABLE-US-00009 Ex. Yield Int. Reactant 50 62% 2a 1-(bromomethyl)-2,3-diclorobenzene (CAS: 57915-78-3). 51 55% 2a 2-chloro-4-fluorobenzyl bromide (CAS: 45767-66-6). 52 46% 2a 2-chloro-3-(trifluoromethyl)benzyl bromide (CAS: 261763-22-8). 53 65% 2a 2,4-difluorobenzyl bromide (CAS: 23915-07-3). 54 58% 2a 4-Fluorobenzyl bromide (CAS: 459-46-1). 55 71% 2g 4-Fluorobenzyl bromide (CAS: 459-46-1). 56 94% 2g 2-Fluorobenzyl bromide (CAS: 446-48-0). 57 90% 2g 3-Methoxybenzyl bromide (CAS: 874-98-6). 58 75% 2g 2-chloro-3-(trifluoromethyl)benzyl bromide (CAS: 261763-22-8). 59 57% 2g 1-(bromomethyl)-2,3-diclorobenzene (CAS: 57915-78-3). 60 70% 2g 2-chloro-4-fluorobenzyl bromide (CAS: 45767-66-6). 61 62% 2g 2,4-difluorobenzyl bromide (CAS: 23915-07-3). 62 51% 2g 2-(Bromomethyl)pyridine hydrobromide (CAS: 31106-82-8). 63 88% 2g 4-(Trifluoromethyl)benzyl bromide (CAS: 402-49-3). 64 72% 2g 3-Bromomethyl-2-methyl-6-trifluoromethyl-pyridine (CAS: 917396-30-6). 65 81% 2g 4-Chlorobenzyl bromide (CAS: 622-95-7). 66 90% 2-(Bromomethyl)-5-(trifluoromethyl)furan (CAS: 17515-77-4). 67 73% 2g 1-(Bromomethyl)-4-methylbenzene (CAS: 104-81-4). 68 97% 2g 1-(Bromomethyl)-4-methoxybenzene (CAS: 2746-25-0). 69 12% 2g bromomethyl)-cyclobutane (CAS: 17247-58-4); reaction conditions: 96 hrs at rt. 70 25% 2g 8-(bromomethyl)-1,4-dioxaspiro[4.5]decane (CAS: 74286-87-6); reaction conditions: 5 days at 60° C. 71 51% 2j 4-Fluorobenzyl bromide (CAS: 459-46-1). 72 61% 2l 4-Fluorobenzyl bromide (CAS: 459-46-1). 73 50% 2n 4-Fluorobenzyl bromide (CAS: 459-46-1). 74 57% 2m 4-Fluorobenzyl bromide (CAS: 459-46-1). 75 78% 2c 4-Fluorobenzyl bromide (CAS: 459-46-1). 76 93% 2f 4-Fluorobenzyl bromide (CAS: 459-46-1). 77 74% 2h 4-Fluorobenzyl bromide (CAS: 459-46-1). 78 50% 2i 4-Fluorobenzyl bromide (CAS: 459-46-1). 79 30% 2r 4-Fluorobenzyl bromide (CAS: 459-46-1). 80 71% 2k 4-Fluorobenzyl bromide (CAS: 459-46-1).
(70) Method D
Preparation of Examples 81-134, Examples 139-147 and Examples 150-251
(71) To a cooled (0° C.) solution of intermediates 2 or 3 (1.0 eq) in DMF (5-12 mL) CH.sub.3ONa (1.5 or 3.0 eq) was added, and the mixture was stirred at same temperature for 10 min. Then, a suitable, commercially available halide (2.5 or 5.0 eq), was added, and the reaction mixture was allowed to warmed to rt, stirred at a suitable temperature for a variable time (see specific examples). The reaction was quenched by adding water and extracted with EtOAc. The organic layers were combined, washed with aqueous saturated NaCl, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by HPLC yielding the pure desired compound. (y=3%-96%)
(72) Using this procedure compounds:
(73) Example 81 (yield 89%) was prepared starting from intermediate 2b and 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2); reaction conditions: o.n. at rt.
(74) Example 82 (yield 64%) was prepared starting from intermediate 2g and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(75) Example 83 (yield 74%) was prepared starting from intermediate 2g and (Bromomethyl)-cyclopropane (CAS: 7051-34-5); reaction conditions: o.n. at rt.
(76) Example 84 (yield 67%) was prepared starting from intermediate 2g and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: o.n. at 70° C.
(77) Example 85 (yield 58%) was prepared starting from intermediate 2g and (Bromomethyl)-cyclopentane (CAS: 3814-30-0); reaction conditions: o.n. at 80° C.
(78) Example 86 (yield 50%) was prepared starting from intermediate 2g and 4-(Bromomethyl)-1,1-dimethylcyclohexane (CAS: 1432681-20-3); reaction conditions: 24 hrs at 60° C.
(79) Example 87 (yield 28%) was prepared starting from intermediate 2g and 1-(Bromomethyl)-1-methylcyclohexane (CAS: 408307-48-2); reaction conditions: 2 weeks at 60° C.
(80) Example 88 (yield 18%) was prepared starting from intermediate 2g and 2-(Bromomethyl)-bicyclo[2.2.1]heptane (CAS: 55932-58-6); reaction conditions: 2 weeks at rt, then 7 days at 60° C.
(81) Example 89 (yield 36%) was prepared starting from intermediate 2g and 3-(Bromomethyl)tetrahydro-2H-pyran (CAS: 116131-44-3); reaction conditions: 5 days at rt.
(82) Example 90 (yield 68%) was prepared starting from intermediate 2g and 1-Bromo-2-pentyne (CAS: 16400-32-1); reaction conditions: 2 hrs at rt.
(83) Example 91 (yield 34%) was prepared starting from intermediate 2g and 1-(Bromomethyl)-bicyclo[2.2.1]heptane (CAS: 61192-17-4); reaction conditions: 5 days at 70° C.
(84) Example 92 (yield 23%) was prepared starting from intermediate 2g and (Bromomethyl)-cycloheptane (CAS: 3814-32-2); reaction conditions: 9 days at rt.
(85) Example 93 (yield 35%) was prepared starting from intermediate 2g and 4-(Bromomethyl)tetrahydro-2H-pyran (CAS: 125552-89-8); reaction conditions: 5 days at rt.
(86) Example 94 (yield 24%) was prepared starting from intermediate 2g and 2-(Bromomethyl)tetrahydro-2H-pyran (CAS: 34723-82-5); reaction conditions: 5 days at rt.
(87) Example 95 (yield 84%) was prepared starting from intermediate 2g and 1-Bromo-2-butyne (CAS: 3355-28-0); reaction conditions: 3 hrs at rt.
(88) Example 96 (yield 3%) was prepared starting from intermediate 2g and 1-(bromomethyl)-1-fluoro-cyclohexane (CAS: 17171-00-5); reaction conditions: 7 days at 70° C.
(89) Example 97 (yield 19%) was prepared starting from intermediate 2g and 2-(bromomethyl)-1,1-difluoro-cyclohexane (CAS: 1817326-97-4); reaction conditions: 5 days at 70° C.
(90) Example 98 (yield 14%) was prepared starting from intermediate 2g and 2-(chloromethyl)-1,4-Dioxane (CAS: 21048-16-8); reaction conditions: 1 month at 60° C.
(91) Example 99 (yield 25%) was prepared starting from intermediate 2g and 2-(bromomethyl)-1,1-dimethyl-cyclohexane (CAS: 1501249-61-1); reaction conditions: 7 days at 60° C.
(92) Example 100 (yield 37%) was prepared starting from intermediate 2g and bromomethoxy-methane (CAS: 13057-17-5); reaction conditions: 5 days at rt.
(93) Example 101 (yield 70%) was prepared starting from intermediate 2g and bromomethoxy-ethane (CAS: 53588-92-4); reaction conditions: o.n. at rt.
(94) Example 102 (yield 37%) was prepared starting from intermediate 2g and 1-(bromomethoxy)-propane (CAS: 59375-50-7); reaction conditions: 4 days at rt.
(95) Example 104 (yield 65%) was prepared starting from intermediate 2p and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(96) Example 105 (yield 90%) was prepared starting from intermediate 2s and 4-Fluorobenzyl bromide, CAS: 459-46-1; reaction conditions: 2 hrs at rt.
(97) Example 107 (yield 77%) was prepared starting from intermediate 2b and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(98) Example 108 (yield 79%) was prepared starting from intermediate 2o and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(99) Example 109 (yield 93%) was prepared starting from intermediate 2d and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(100) Example 110 (yield 28%) was prepared starting from intermediate 2p and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 24 hrs at rt, then 24 hrs at 60° C.
(101) Example 111 (yield 29%) was prepared starting from intermediate 2r and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at rt, then 3 hrs at 80° C.
(102) Example 112 (yield 88%) was prepared starting from intermediate 2e and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(103) Example 113 (yield 59%) was prepared starting from intermediate 2l and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(104) Example 114 (yield 84%) was prepared starting from intermediate 2n and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(105) Example 115 (yield 31%) was prepared starting from intermediate 2j and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 48 hrs at 60° C.
(106) Example 116 (yield 50%) was prepared starting from intermediate 2s and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(107) Example 117 (yield 61%) was prepared starting from intermediate 2f and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(108) Example 118 (yield 29%) was prepared starting from intermediate 2m and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(109) Example 119 (yield 80%) was prepared starting from intermediate 2k and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(110) Example 120 (yield 89%) was prepared starting from intermediate 2c and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(111) Example 121 (yield 53%) was prepared starting from intermediate 2h and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(112) Example 122 (yield 50%) was prepared starting from intermediate 2i and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(113) Example 123 (yield 21%) was prepared starting from intermediate 2q and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(114) Example 125 (yield 78%) was prepared starting from intermediate 2b and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(115) Example 126 (yield 75%) was prepared starting from intermediate 2o and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(116) Example 127 (yield 90%) was prepared starting from intermediate 2d and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(117) Example 128 (yield 70%) was prepared starting from intermediate 2g and 3-(bromomethyl)-1,1-difluorocyclopentane (CAS: 1695914-13-6); reaction conditions: 24 hrs at 60° C.
(118) Example 129 (yield 96%) was prepared starting from intermediate 2u and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(119) Example 130 (yield 93%) was prepared starting from intermediate 2u and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at rt.
(120) Example 131 (yield 85%) was prepared starting from intermediate 2u and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(121) Example 132 (yield 91%) was prepared starting from intermediate 2v and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at rt.
(122) Example 133 (yield 64%) was prepared starting from intermediate 2v and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(123) Example 134 (yield 50%) was prepared starting from intermediate 2v and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(124) Example 139 (yield 48%) was prepared starting from intermediate 3a and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: o.n. at rt.
(125) Example 140 (yield 24%) was prepared starting from intermediate 3a and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(126) Example 141 (yield 44%) was prepared starting from intermediate 3a and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: o.n. at 60° C.
(127) Example 142 (yield 59%) was prepared starting from intermediate 2g and 1-Bromo-2-cyclohexylethane (CAS: 1647-26-3); reaction conditions: o.n. at 60° C.
(128) Example 143 (yield 45%) was prepared starting from intermediate 2g and 1-(2-Bromoethyl)piperidine (CAS: 56477-57-7); reaction conditions: o.n. at 60° C.
(129) Example 144 (yield 76%) was prepared starting from intermediate 2w and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 2 hrs at 60° C.
(130) Example 145 (yield 60%) was prepared starting from intermediate 2w and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(131) Example 146 (yield 69%) was prepared starting from intermediate 2w and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 48 hrs at 50° C.
(132) Example 147 (yield 19%) was prepared starting from intermediate 2w and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(133) Example 150 (yield 69%) was prepared starting from intermediate 2c and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(134) Example 151 (yield 47%) was prepared starting from intermediate 2b and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(135) Example 152 (yield 44%) was prepared starting from intermediate 2a and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(136) Example 153 (yield 56%) was prepared starting from intermediate 2k and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(137) Example 154 (yield 33%) was prepared starting from intermediate 2e and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(138) Example 155 (yield 39%) was prepared starting from intermediate 2l and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(139) Example 156 (yield 57%) was prepared starting from intermediate 2j and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(140) Example 157 (yield 48%) was prepared starting from intermediate 2s and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(141) Example 158 (yield 40%) was prepared starting from intermediate 2f and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(142) Example 159 (yield 42%) was prepared starting from intermediate 2m and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(143) Example 160 (yield 62%) was prepared starting from intermediate 2d and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(144) Example 161 (yield 63%) was prepared starting from intermediate 2o and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(145) Example 162 (yield 48%) was prepared starting from intermediate 2n and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 48 hrs at 50° C.
(146) Example 163 (yield 47%) was prepared starting from intermediate 2u and 1-(1-Bromoethyl)-4-fluorobenzene (CAS: 65130-46-3); reaction conditions: 24 hrs at rt.
(147) Example 164 (yield 48%) was prepared starting from intermediate 2v and 1-(1-Bromoethyl)-4-fluorobenzene (CAS: 65130-46-3); reaction conditions: 24 hrs at rt.
(148) Example 165 (yield 72%) was prepared starting from intermediate 2v and 2-Fluorobenzyl bromide (CAS: 446-48-0); reaction conditions: o.n. at 60° C.
(149) Example 166 (yield 84%) was prepared starting from intermediate 2v and 4-(Trifluoromethyl)benzyl bromide (CAS: 402-49-3); reaction conditions: o.n. at 60° C.
(150) Example 167 (yield 71%) was prepared starting from intermediate 2v and 2-chloro-3-(trifluoromethyl)benzyl bromide (CAS: 261763-22-8); reaction conditions: o.n. at 60° C.
(151) Example 168 (yield 75%) was prepared starting from intermediate 2v and 2-(Bromomethyl)-5-(trifluoromethyl)furan (CAS: 17515-77-4); reaction conditions: 2 hrs at rt.
(152) Example 169 (yield 74%) was prepared starting from intermediate 2v and 3-Bromomethyl-5-methyl-isoxazole (CAS: 130628-75-0); reaction conditions: 2 hrs at rt.
(153) Example 170 (yield 86%) was prepared starting from intermediate 2v and 2-chlorobenzyl chloride (CAS: 611-19-8); reaction conditions: o.n. at 60° C.
(154) Example 171 (yield 65%) was prepared starting from intermediate 2v and (1-chloromethyl)-4-fluoro-2-methylbenzene (CAS: 80141-92-0); reaction conditions: o.n. at 60° C.
(155) Example 172 (yield 53%) was prepared starting from intermediate 2v and (2-Bromoethyl)benzene (CAS: 103-63-9); reaction conditions: o.n. at 60° C.
(156) Example 173 (yield 55%) was prepared starting from intermediate 2g and 3-(bromomethyl)-6,6-difluorobicyclo[3.1.0]hexane (CAS: 1393569-74-8); reaction conditions: o.n. at 60° C.
(157) Example 174 (yield 95%) was prepared starting from intermediate 2g and Iodomethane (CAS: 74-88-4); reaction conditions: 2 hrs at rt.
(158) Example 175 (yield 58%) was prepared starting from intermediate 2g and Bromoethane (CAS: 74-96-4); reaction conditions: 2 hrs at rt.
(159) Example 176 (yield 71%) was prepared starting from intermediate 2g and 1-bromopropane (CAS: 106-94-5); reaction conditions: o.n. at 60° C.
(160) Example 177 (yield 86%) was prepared starting from intermediate 2g and 1-bromobutane (CAS: 109-65-9); reaction conditions: o.n. at 60° C.
(161) Example 178 (yield 38%) was prepared starting from intermediate 2g and 1-Bromo-2-methylpropane (CAS: 78-77-3); reaction conditions: 3 days at 60° C.
(162) Example 179 (yield 84%) was prepared starting from intermediate 2g and 3-cyclohexylpropyl bromide (CAS: 34094-21-8); reaction conditions: o.n. at 60° C.
(163) Example 180 (yield 75%) was prepared starting from intermediate 2g and 1-(3-bromopropyl)piperidine hydrobromide (CAS: 58689-34-2); reaction conditions: 2 days at 60° C.
(164) Example 181 (yield 18%) was prepared starting from intermediate 2g and 1-(2-bromoethyl)-4,4-difluoropiperidine hydrobromide (CAS: 1996969-81-3); reaction conditions: 2 days at 60° C.
(165) Example 182 (yield 26%) was prepared starting from intermediate 2g and 1-(3-bromopropyl)-4,4-difluoropiperidine hydrobromide (CAS: 1782084-16-5); reaction conditions: 2 days at 60° C.
(166) Example 183 (yield 57%) was prepared starting from intermediate 2g and 4-(bromomethyl)-1-cyclopentene (CAS: 80864-33-1); reaction conditions: 2 hrs at rt and o.n. at 60° C.
(167) Example 184 (yield 47%) was prepared starting from intermediate 2g and 1-(bromomethyl)-4-(trifluoromethyl)cyclohexane (CAS: 858121-96-7); reaction conditions: o.n. at 60° C.
(168) Example 185 (yield 56%) was prepared starting from intermediate 2g and 1-(bromomethyl)-4-fluorocyclohexane (CAS: 1784609-74-0); reaction conditions: o.n. at 60° C.
(169) Example 186 (yield 23%) was prepared starting from intermediate 2kk and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(170) Example 187 (yield 23%) was prepared starting from intermediate 2kk and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(171) Example 188 (yield 18%) was prepared starting from intermediate 2v and 1-chloroethylbenzene (CAS: 672-65-1); reaction conditions: one week at 60° C.
(172) Example 189 (yield 76%) was prepared starting from intermediate 2v and 5-Chloromethyl-2-(trifluoromethyl)pyridine (CAS: 386715-33-9); reaction conditions: 3 days at 60° C.
(173) Example 190 (yield 83%) was prepared starting from intermediate 2v and 2-(chloromethyl)-5-fluoropyrimidine (CAS: 1196151-61-7); reaction conditions: 3 days at 60° C.
(174) Example 191 (yield 47%) was prepared starting from intermediate 2v and 2-(Chloromethyl)thiazole (CAS: 3364-78-1); reaction conditions: 3 days at 60° C.
(175) Example 192 (yield 84%) was prepared starting from intermediate 2v and 3-Bromomethyl-2-methyl-6-trifluoromethyl-pyridine (CAS: 917396-30-6); reaction conditions: 4 hrs at rt.
(176) Example 193 (yield 41%) was prepared starting from intermediate 2v and 5-(Chloromethyl)thiazole hydrochloride (CAS: 131052-44-3); reaction conditions: o.n. at 60° C.
(177) Example 194 (yield 46%) was prepared starting from intermediate 2v and 2-Chloromethyl-oxazole (CAS: 185246-17-7); reaction conditions: o.n. at 60° C.
(178) Example 195 (yield 39%) was prepared starting from intermediate 2v and 5-(Chloromethyl)-1,3-dimethyl-1H-pyrazole (CAS: 852227-86-2); reaction conditions: o.n. at 60° C.
(179) Example 196 (yield 45%) was prepared starting from intermediate 2v and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (CAS: 1192-80-9); reaction conditions: o.n. at 60° C.
(180) Example 197 (yield 29%) was prepared starting from intermediate 2v and 5-(Chloromethyl)-3-methyl-1,2,4-oxadiazole (CAS: 1192-81-0); reaction conditions: o.n. at 60° C.
(181) Example 198 (yield 37%) was prepared starting from intermediate 2v and 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole (CAS: 860807-20-1); reaction conditions: o.n. at 60° C.
(182) Example 199 (yield 35%) was prepared starting from intermediate 2v and 5-(Chloromethyl)oxazole (CAS: 172649-57-9); reaction conditions: o.n. at 60° C.
(183) Example 200 (yield 54%) was prepared starting from intermediate 2v and Thiazole, 5-(chloromethyl)-4-methyl-, hydrochloride (CAS 1301739-54-7); reaction conditions: o.n. at 60° C.
(184) Example 201 (yield 35%) was prepared starting from intermediate 2v and 2-(Chloromethyl)-1-methyl-1H-imidazole hydrochloride (CAS 19225-92-4); reaction conditions: o.n. at rt.
(185) Example 202 (yield 39%) was prepared starting from intermediate 3b and 4-Fluorobenzyl bromide (CAS 459-46-1); reaction conditions: 3 hrs at rt.
(186) Example 203 (yield 21%) was prepared starting from intermediate 3b and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at rt.
(187) Example 204 (yield 70%) was prepared starting from intermediate 2gg and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(188) Example 205 (yield 67%) was prepared starting from intermediate 2gg and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at 60° C.
(189) Example 206 (yield 62%) was prepared starting from intermediate 2gg and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 24 hrs at 60° C.
(190) Example 207 (yield 70%) was prepared starting from intermediate 2gg and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 24 hrs at 60° C.
(191) Example 208 (yield 72%) was prepared starting from intermediate 2ll and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(192) Example 209 (yield 86%) was prepared starting from intermediate 2ll and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at 60° C.
(193) Example 210 (yield 28%) was prepared starting from intermediate 2ll and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 2 hrs at rt.
(194) Example 211 (yield 31%) was prepared starting from intermediate 2ll and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 2 hrs at rt.
(195) Example 212 (yield 41%) was prepared starting from intermediate 2 mm and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 24 hrs at rt.
(196) Example 213 (yield 32%) was prepared starting from intermediate 2 mm and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at 60° C.
(197) Example 214 (yield 39%) was prepared starting from intermediate 2 mm and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 60° C.
(198) Example 215 (yield 46%) was prepared starting from intermediate 2 mm and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: o.n. at 60° C.
(199) Example 216 (yield 29%) was prepared starting from intermediate 2x and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(200) Example 217 (yield 49%) was prepared starting from intermediate 2x and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at 60° C.
(201) Example 218 (yield 37%) was prepared starting from intermediate 2x and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 24 hrs. at 60° C.
(202) Example 219 (yield 36%) was prepared starting from intermediate 2x and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 34 hrs at 60° C.
(203) Example 220 (yield 20%) was prepared starting from intermediate 2y and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at rt.
(204) Example 221 (yield 22%) was prepared starting from intermediate 2y and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 2 hrs at rt.
(205) Example 222 (yield 26%) was prepared starting from intermediate 2y and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: 24 hrs. at 60° C.
(206) Example 223 (yield 20%) was prepared starting from intermediate 2y and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 34 hrs at 60° C.
(207) Example 224 (yield 58%) was prepared starting from intermediate 2z and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(208) Example 225 (yield 83%) was prepared starting from intermediate 2z and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(209) Example 226 (yield 53%) was prepared starting from intermediate 2cc and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(210) Example 227 (yield 68%) was prepared starting from intermediate 2cc and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(211) Example 228 (yield 37%) was prepared starting from intermediate 2hh and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(212) Example 229 (yield 48%) was prepared starting from intermediate 2hh and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at rt.
(213) Example 230 (yield 30%) was prepared starting from intermediate 2hh and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(214) Example 231 (yield 36%) was prepared starting from intermediate 2hh and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: o.n. at 70° C.
(215) Example 232 (yield 34%) was prepared starting from intermediate 2dd and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(216) Example 233 (yield 28%) was prepared starting from intermediate 2dd and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(217) Example 234 (yield 23%) was prepared starting from intermediate 2dd and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(218) Example 235 (yield 23%) was prepared starting from intermediate 2dd and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: o.n. at 70° C.
(219) Example 236 (yield 54%) was prepared starting from intermediate 2ii and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(220) Example 237 (yield 55%) was prepared starting from intermediate 2ii and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(221) Example 238 (yield 41%) was prepared starting from intermediate 2ii and (Bromomethyl)cyclohexane (CAS: 2550-36-9); reaction conditions: o.n. at 70° C.
(222) Example 239 (yield 44%) was prepared starting from intermediate 2ii and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: o.n. at 70° C.
(223) Example 240 (yield 19%) was prepared starting from intermediate 2aa and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(224) Example 241 (yield 66%) was prepared starting from intermediate 2aa and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(225) Example 242 (yield 65%) was prepared starting from intermediate Zee and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(226) Example 243 (yield 36%) was prepared starting from intermediate Zee and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: 3 hrs at rt.
(227) Example 244 (yield 32%) was prepared starting from intermediate 2bb and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(228) Example 245 (yield 19%) was prepared starting from intermediate 2bb and 4-(bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5); reaction conditions: 2 days at 50° C.
(229) Example 246 (yield 11%) was prepared starting from intermediate 2ff and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: 3 hrs at rt.
(230) Example 247 (yield 20%) was prepared starting from intermediate 2jj and 4-Fluorobenzyl bromide (CAS: 459-46-1); reaction conditions: o.n. at rt
(231) Example 248 (yield 20%) was prepared starting from intermediate 2jj and 2-chloro-6-fluorobenzylchloride (CAS: 55117-15-2); reaction conditions: o.n. at rt
(232) Example 249 (yield 25%) was prepared starting from intermediate 2jj and (Bromomethyl)cyclohexane; CAS: 2550-36-9; reaction conditions: o.n. at 70° C.
(233) Example 250 (yield 30%) was prepared starting from intermediate 2jj and 4-(Bromomethyl)-1,1-difluorocyclohexane (CAS: 858121-94-5), reaction conditions: o.n. at 70° C.
(234) Example 251 (yield 35%) was prepared starting from intermediate 2jj and 3-(bromomethyl)-1,1-difluorocyclopentane; CAS: 1695914-13-6; reaction conditions: o.n. at 70° C.
(235) Method E
Preparation of Examples 135-138
(236) To a mixture of intermediate 2 (1.0 eq), Cs.sub.2CO.sub.3 (1.0 eq) and NaI (0.05 eq) in DMSO (5-12 mL) a suitable, commercially available halide (0.75 or 1.0 eq) was added dropwise, and the reaction mixture was stirred at r.t. for 3 hrs. The reaction mixture was quenched by addition of NH.sub.4Cl and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. The crude product was purified by HPLC giving the pure desired compound. (y=19%-39%)
(237) Using this procedure compounds:
(238) Example 135 (yield 33%) was prepared starting from intermediate 2l and 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2).
(239) Example 136 (yield 27%) was prepared starting from intermediate 2l and benzyl chloride (CAS: 100-44-7).
(240) Example 137 (yield 39%) was prepared starting from intermediate 2k and 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2).
(241) Example 138 (yield 19%) was prepared starting from intermediate 2j and 2-chloro-6-fluorobenzyl chloride (CAS: 55117-15-2).
Preparation of Examples 148-149
(242) Example 148 and example 149 compounds, were obtained by enantiomeric separation of the racemate of Example 128; for separation procedures, see analytical methods.
(243) Table 1 lists final compounds that were prepared according to the experimental procedure described for Example 1.
(244) TABLE-US-00010 TABLE 1 Example Structure IUPAC Name 1
(245) Purification System
(246) HPLC Preparative
(247) HPLC system WATERS Quaternary Gradient Mobile 2535 equipped with WATERS UV/Visible Detector 2489 set to a dual-wavelength UV detection. Two mobile phases were used, mobile phase A: water (MilliQ) 0.05% TFA; mobile phase B: acetonitrile (Chromasolv Sigma-Aldrich) 0.05% TFA, and the run gradient conditions were set specifically for each compound. The purifications were achieved on a LUNA C18 Phenomenex Column 5 μm 19×150. An injection volume between 100 and 500 μl was used and the flow was 15 ml/min.
(248) Racemate Separation
(249) The two enantiomers 148 and 149 were obtained by resolution of the racemic mixture 128 using a WATERS Quaternary Gradient Mobile 2535 equipped with WATERS UV/Visible Detector 2489 set to a dual-wavelength UV detection at 220 and 260 nm. The chiral resolution was achieved on the Kromasil 5-Amycoat column (250 mm×4.6 mm, particle size 5 μm) using N-Hexane (Chromasolv Sigma-Aldrich)—Ethanol (Chromasolv Sigma-Aldrich) 90-10 (v/v) as isocratic mobile phase; The sample was eluted from the column at a flow rate of 1.0 ml/min at room temperature (Pressure: ≈600 psi). The mixture was dissolved in Ethanol at concentration of 1% (w/v) and the injection volume was 15 μL.
(250) LCMS
(251) LCMS General Procedure
(252) The HPLC measurement was performed using a Dionex 3000 module comprising a quaternary pump with degasser, an autosampler, a column oven (set at 29° C.), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (LCQ Fleet Thermo Scientific) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 50 to 800 in 0.48 second. The capillary needle voltage was 5 kV in positive and negative ionization mode and the source temperature was maintained at 275° C. Nitrogen was used as the nebulizer gas, the flow was 8 l/min. Data acquisition was performed with Thermo Xcalibur Qual Browser.
(253) LCMS—Procedure
(254) In addition to the general procedure, reversed-phase HPLC was carried out on a Kinetex XB-C.sub.18 column Phenomenex (1.7 μm, 50×2.1 mm) with a flow rate of 0.300 ml/min. Two mobile phases were used, mobile phase A: ammonium formate buffer solution at pH 3.5; mobile phase B: acetonitrile (Chromasolv Sigma-Aldrich), and they were employed to run a gradient conditions from 15% B to 98% in 4.5 minutes, hold these condition for 1.35 minutes and then 15% B in 0.1 minutes and hold these conditions for 3 minutes in order to reequilibrate the column. An injection volume of 1 μl was used.
(255) TABLE-US-00011 TABLE 2 Retention time (R.sub.t) in minutes, [M + H]+, [M − H].sup.− and [M − H + HCOOH].sup.− peaks observed in LCMS procedure. Example R.sub.t [M + H].sup.+ [M − H].sup.− [M − H + HCOOH].sup.− Example R.sub.t [M + H].sup.+ [M − H].sup.− [M − H + HCOOH].sup.− 1 4.80 337.8 — — 2 4.94 — 343.6 — 3 4.80 — 313.7 — 4 5.27 345.2 — 389.0 5 5.49 — — 426.2 6 5.39 319.1 — — 7 5.34 349.64 — — 8 4.52 306.3 — 350.3 9 5.68 — — 397.92 10 5.38 299.1 — — 11 5.38 — — 361.1 12 5.63 291.2 — — 13 5.81 388.2 — — 14 5.59 372.4 — — 15 5.45 355.6 — — 16 5.84 — 420.2 — 17 5.88 388.3 386.6 — 18 5.50 371.9 — — 19 5.36 337.1 — — 20 5.52 354.2 — — 21 5.43 319.4 — — 22 5.61 353.8 — — 23 5.72 387.8 — — 24 4.24 334.5 — — 25 5.57 351.1 — — 26 5.41 337.3 — — 27 5.59 333.3 — — 28 5.48 349.9 — — 29 5.75 369.1 — — 30 4.84 370.7 — — 31 4.72 340.5 — — 32 4.55 310.3 — — 33 4.59 326.1 — — 34 4.82 326.5 — — 35 5.44 — — 421.1 36 4.87 338.2 — — 37 5.26 — — 432.4 38 4.09 321.2 — — 39 4.42 321.5 — — 40 4.45 310.3 — — 41 4.40 325.8 — — 42 4.34 320.4 — — 43 4.13 320.4 — — 44 5.08 309.1 — — 45 4.77 339.8 — — 46 4.66 337.3 — — 47 2.67 323.4 — — 48 5.52 351.1 — — 49 5.50 339.9 — — 50 5.64 — — 398.5 51 5.48 — — 381.8 52 5.67 — — 431.6 53 5.32 321.6 — 366.2 54 5.26 303.0 — 347.0 55 5.48 337.5 — — 56 5.43 337.1 — — 57 5.41 349.6 — — 58 5.82 422.3 — — 59 5.79 388.3 — — 60 5.68 372.1 — — 61 5.49 355.3 — — 62 4.80 320.4 — — 63 5.68 387.0 — — 64 5.35 402.1 — 445.9 65 5.60 — — 398.2 66 5.47 377.1 — — 67 5.56 333.3 — — 68 5.32 349.1 — — 69 5.41 296.9 — — 70 5.10 383.0 — — 71 5.66 — 352.3 398.1 72 5.71 — 385.7 431.2 73 5.50 337.2 — — 74 5.73 — 352.0 398.1 75 5.24 303.0 — — 76 5.41 319.1 — — 77 5.73 365.8 — — 78 5.56 351.1 — — 79 4.04 286.1 — — 80 5.34 321.2 — 365.1 81 5.35 337.1 — — 82 5.80 325.7 — — 83 5.13 283.0 — — 84 5.42 — — 405.1 85 5.62 311.0 — — 86 5.84 353.7 351.2 — 87 6.09 339.8 — — 88 5.92 337.2 — — 89 4.95 327.2 — — 90 5.35 295.3 — — 91 5.94 337.7 — — 92 6.10 339.0 — — 93 4.73 344.8 — — 94 5.50 327.0 — — [M + H.sub.3O].sup.+ 95 5.08 281.0 — — 96 5.72 343.2 — — 97 5.54 361.1 — — 98 4.74 329.1 — — 99 6.25 353.4 — — 100 4.78 273.3 — — 101 5.05 287.4 — — 102 5.37 301.1 — — 104 4.45 286.1 — — 105 5.46 353.01 — 397.4 107 5.23 — — 347.0 108 5.20 285.0 — — 109 5.21 315.0 — — 110 4.87 274.1 — — 111 4.51 274.1 — — 112 5.59 303.6 — — 113 6.06 375.1 — — 114 5.94 — — 368.6 115 6.15 — 340.9 — 116 5.94 341.4 — — 117 5.84 307.3 — — 118 6.24 — 340.5 — 119 5.65 309.2 — — 120 5.63 291.2 — — 121 6.25 353.9 — — 122 6.08 339.2 — — 123 4.54 274.3 — — 125 5.63 291.0 — — 126 5.63 273.2 — — 127 5.56 303.2 — — 128 5.34 347.2 — — 129 6.22 279.6 — — 130 5.95 325.8 — — 131 5.75 291.4 — — 132 5.38 360.9 — — 133 5.28 — — 358.1 134 5.44 — — 370.9 135 5.47 — 873.4 — 136 5.40 — 767.6 — [Dimer] [Dimer] 137 5.14 — 740.7 — 138 5.44 — 806.2 — [Dimer] [Dimer] 139 5.65 353.0 — — 140 6.26 341.3 — — 141 5.76 377.1 — — 142 6.21 339.3 — — 143 3.50 340.2 — — 144 5.79 386.5 — — 145 5.72 351.1 — — 146 6.17 339.1 — — 147 5.75 375.1 — — 148 5.34 347.2 — — 149 5.34 347.2 — — 150 5.38 — — — 151 5.40 — — 370.9 152 5.40 — — 371.0 153 5.45 — — — 154 5.36 — — — 155 5.68 — 409.4 — 156 5.65 — 376.9 — 157 5.55 — 375.9 — 158 5.46 — — 386.8 159 5.73 — 376.2 — 160 5.29 339.1 — 383.1 161 5.28 309.2 — 353.2 162 5.49 — — 405.4 163 5.80 305.7 — 349.9 164 5.46 — — 385.2 165 5.34 — — 361.0 166 5.62 — — 421.3 167 5.74 — — 455.6 168 5.42 — — 411.1 169 4.98 — 312.0 — 170 5.51 — — — 171 5.50 — — 385.2 172 5.42 — — 366.9 173 5.46 359.1 — — 174 4.44 243.0 — — 175 4.75 257.0 — — 176 5.05 271.0 — — 177 5.31 285.0 — — 178 5.28 285.0 — — 179 6.36 353.2 — 397.4 180 2.46 354.43 181 5.20 376.5 — — 182 4.01 390.5 — — 183 5.44 309.0 — — 184 5.73 — 391.0 — 185 5.34 343.1 — — 186 5.35 296.7 — — 187 5.50 331.2 188 5.46 — — 367.1 189 5.26 378.1 — 422.1 190 4.85 329.2 327.3 — 191 4.87 316.2 — — 192 5.37 392.3 — 436.1 193 4.55 — — 360.0 194 4.62 300.1 — 344.3 195 4.67 327.2 — 371.0 196 4.74 315.1 — 359.5 197 4.76 — — 359.3 198 5.39 — — 411.0 199 4.71 — — 344.2 200 4.73 330.2 — 374.0 201 4.01 313.1 — — 202 5.60 — — 387.2 203 5.72 377.0 — 421.6 204 5.27 — — 357.8 205 5.35 347.0 — — 206 5.15 301.1 — — 207 — — — 381.2 208 4.75 — — 348.2 209 4.88 338.1 — 372.1 210 5.13 292.2 — 336.6 211 4.91 — — 372.4 212 4.50 317.2 — — 213 4.57 351.5 — — 214 4.81 305.4 — — 215 4.57 341.4 — — 216 4.02 300.3 — 343.8 217 4.08 334.5 — — 218 4.54 288.4 — — 219 4.18 324.4 — 368.2 220 5.39 362.2 — — 221 5.29 328.1 — 372.2 222 — 316.2 — — 223 — — — 396.2 224 5.31 362.3 — — 225 5.25 328.1 226 5.51 376.3 — — 227 5.37 342.1 — 386.1 228 5.28 342.0 — 386.1 229 5.34 376.0 — — 230 5.61 330.1 — — 231 5.32 366.1 — 410.3 232 5.59 346.1 — — 233 5.72 380.3 — — 234 5.98 334.2 — — 235 5.57 370.2 — 414.3 236 5.60 369.2 — 403.1 237 5.76 403.4 — — 238 6.06 357.4 — — 239 5.63 393.2 — 437.0 240 5.26 292.1 — — 241 5.47 326.3 — — 242 6.51 416.5 — — 243 6.32 382.3 — — 244 5.81 374.3 — — 245 5.63 330.1 — — 246 3.07 312.2 — — 247 4.50 306.1 — 349.7 248 4.60 340.1 — — 249 4.88 294.2 — — 250 4.63 — — 373.8 251 5.00 — — 359.6
(256) NMR Characterization
(257) .sup.1H NMR spectra were recorded on a Varian Mercury NMR 400 MHz spectrometer using CDCl.sub.3, DMSO-d6 or CD.sub.3OD as solvents Chemical shifts (6) are reported in parts per million (ppm) relative to residual signal of non-fully deuterated solvents pick for .sup.1H NMR assigned as 7.26 ppm for CHCl.sub.3, 3.31 ppm for CHD.sub.2OD and 2.50 ppm for DMSO-d.sub.5.
(258) TABLE-US-00012 Example .sup.1H-NMR 400 1 .sup.1H NMR (CD.sub.3OD) δ ppm 3.96 (s, 2 H) 4.97 (s, 2 H) 6.95 (t, J = 8.71 Hz, 2 H) 7.01 (t, J = 9.29 Hz, 1 H) 7.14 (dd, J = 8.31, 5.38 Hz, 2 H) 7.19 (d, J = 8.22 Hz, 1 H) 7.25-7.33 (m, 1 H) 2 .sup.1H NMR (CDCl.sub.3) δ ppm 3.77 (s, 3 H) 3.79 (s, 3 H) 4.02 (s, 2 H) 4.95 (s, 2 H) 6.41-6.48 (m, 2 H) 7.01 (t, J = 8.48 Hz, 2 H) 7.12 (d, J = 7.97 Hz, 1 H) 7.22-7.30 (m, 2 H) 3 .sup.1H NMR (CDCl.sub.3) δ ppm 3.79 (s, 3 H) 3.95 (s, 2 H) 4.92 (s, 2 H) 6.84 (d, J = 8.52 Hz, 2 H) 6.95-7.11 (m, 3 H) 7.14-7.34 (m, 1 H) 7.37-7.51 (m, 1 H) 7.66 (br dd, J = 11.82, 7.70 Hz, 1 H) 4 .sup.1H NMR (CDCl.sub.3) δ ppm 3.71-3.76 (m, 8 H) 4.47 (s, 2 H) 6.16-6.23 (m, 2 H) 6.36 (s, 1 H) 6.99 (t, J = 8.05 Hz, 2 H) 7.05-7.17 (m, 2 H) 5 .sup.1H NMR (CDCl.sub.3) δ ppm 3.82 (s, 2 H) 4.68 (s, 2 H) 6.53 (dd, J = 8.84, 2.43 Hz, 1 H) 6.83-7.00 (m, 3 H) 7.10 (dd, J = 7.97, 5.41 Hz, 2 H) 7.49 (dd, J = 8.71, 5.13 Hz, 1 H) 6 .sup.1H NMR (CDCl.sub.3) δ ppm 3.89 (s, 2 H) 4.79 (s, 2 H) 6.95 (s, 1 H) 7.14 (br t, J = 6.69 Hz, 3 H) 7.19-7.34 (m, 4 H) 7 .sup.1H NMR (CDCl.sub.3) δ ppm 3.77 (s, 3 H) 3.87 (s, 2 H) 4.79 (s, 2 H) 6.65 (br s, 1 H) 6.71 (br d, J = 7.43 Hz, 2 H) 6.94 (s, 1 H) 7.09-7.30 (m, 3 H) 8 .sup.1H NMR (CDCl.sub.3) δ ppm 2.41 (s, 3 H) 3.88 (s, 2 H) 4.71 (s, 2 H) 7.05 (t, J = 8.48 Hz, 2 H) 7.18 (br dd, J = 8.16, 5.32 Hz, 2 H) 8.65 (s, 1 H) 9 .sup.1H NMR (CDCl.sub.3) δ ppm 3.80 (s, 2 H) 4.69 (s, 2 H) 6.91 (d, J = 8.34 Hz, 1 H) 6.96 (t, J = 8.48 Hz, 2 H) 7.07-7.13 (m, 2 H) 7.17 (dd, J = 8.34, 1.83 Hz, 1 H) 7.37 (d, J = 1.83 Hz, 1 H) 10 .sup.1H NMR (CDCl.sub.3) δ ppm 1.66 (d, J = 7.24 Hz, 3 H) 3.63-3.78 (m, 2 H) 5.07 (d, J = 7.24 Hz, 1 H) 7.01 (t, J = 8.10 Hz, 2 H) 7.10 (dd, J = 8.43, 5.32 Hz, 2 H) 7.17-7.27 (m, 2 H) 7.27-7.40 (m, 3 H) 11 .sup.1H NMR (CDCl.sub.3) δ ppm 1.65 (d, J = 7.24 Hz, 3 H) 3.78 (d, J = 5.96 Hz, 2 H) 5.00 (br d, J = 7.24 Hz, 1 H) 6.94-7.07 (m, 4 H) 7.08-7.27 (m, 4 H) 12 .sup.1H NMR (CDCl.sub.3) δ ppm 0.77-0.94 (m, 2 H) 1.10 (br s, 3 H) 1.39-1.51 (m, 1 H) 1.51-1.75 (m, 5 H) 3.20 (d, J = 7.42 Hz, 2 H) 3.89 (s, 2 H) 7.05 (t, J = 8.48 Hz, 2 H) 7.15-7.28 (m, 2 H) 13 .sup.1H NMR (CDCl.sub.3) δ ppm 3.96 (s, 2 H) 4.92 (s, 2 H) 6.92-7.01 (m, 2 H) 7.08-7.16 (m, 2 H) 7.18-7.25 (m, 1 H) 7.35 (d, J = 7.15 Hz, 1 H) 14 .sup.1H NMR (CDCl.sub.3) δ ppm 3.89 (s, 2 H) 4.92 (s, 2 H) 6.89 (td, J = 8.23, 2.52 Hz, 1 H) 6.97 (t, J = 8.94 Hz, 1 H) 7.04-7.10 (m, 2 H) 7.13-7.18 (m, 1 H) 7.20-7.26 (m, 1 H) 15 .sup.1H NMR (CDCl.sub.3) δ ppm 3.83 (s, 2 H) 4.91 (s, 2 H) 6.71-6.86 (m, 2 H) 6.98 (t, J = 8.89 Hz, 1 H) 7.05-7.29 (m, 3 H) 16 .sup.1H NMR (CDCl.sub.3) δ ppm 3.99 (s, 2 H) 4.95 (s, 2 H) 6.93 (t, J = 8.94 Hz, 1 H) 7.08-7.13 (m, 1 H) 7.14-7.22 (m, 1 H) 7.24-7.31 (m, 2 H) 7.56-7.61 (m, 1 H) 17 .sup.1H NMR (CDCl.sub.3) δ ppm 3.90 (s, 2 H) 4.92 (s, 2 H) 6.96 (t, J = 8.98 Hz, 1 H) 7.01 (d, J = 8.25 Hz, 1 H) 7.11-7.18 (m, 2 H) 7.21-7.28 (m, 1 H) 7.33 (d, J = 1.83 Hz, 1 H) 18 .sup.1H NMR (CDCl.sub.3) δ ppm 3.91 (d, J = 1.01 Hz, 2 H) 5.02-5.14 (m, 2 H) 6.97-7.04 (m, 1 H) 7.05-7.12 (m, 1 H) 7.20 (t, J = 7.24 Hz, 1 H) 7.23-7.30 (m, 2 H) 7.31-7.39 (m, 1 H) 19 .sup.1H NMR (CDCl.sub.3) δ ppm 3.89 (s, 2 H) 4.88 (s, 2 H) 6.92-7.18 (m, 5 H) 7.19-7.29 (m, 2 H) 20 .sup.1H NMR (CDCl.sub.3) δ ppm 3.95 (s, 2 H) 4.90 (s, 2 H) 6.96 (t, J = 8.89 Hz, 1 H) 7.06-7.11 (m, 1 H) 7.12-7.24 (m, 4 H) 7.33 (dd, J = 7.47, 1.60 Hz, 1 H) 21 .sup.1H NMR (CD3OD) δ ppm 4.06 (s, 2 H) 4.94 (s, 2 H) 7.07 (t, J = 9.00 Hz, 1 H) 7.20-7.25 (m, 1 H) 7.30 (br d, J = 7.04 Hz, 3 H) 7.33-7.42 (m, 3 H) 22 .sup.1H NMR (CDCl.sub.3) δ ppm 3.94 (s, 2 H) 4.96 (s, 2 H) 6.91-6.98 (m, 1 H) 7.08-7.21 (m, 3 H) 7.23-7.31 (m, 2 H) 7.37-7.42 (m, 1 H) 23 .sup.1H NMR (CDCl.sub.3) δ ppm 3.89 (m, 2 H) 5.10 (s, 2 H) 6.91-6.99 (m, 1 H) 7.11-7.24 (m, 3 H) 7.43-7.50 (m, 1 H) 7.54-7.60 (m, 1 H) 7.73 (d, J = 7.70 Hz, 1 H) 24 .sup.1H NMR (CDCl.sub.3) δ ppm 2.54 (s, 3 H) 3.93 (s, 2 H) 4.83 (s, 2 H) 6.87-6.94 (m, 1 H) 7.05-7.20 (m, 4 H) 8.42 (br d, J = 3.85 Hz, 1 H) 25 .sup.1H NMR (CDCl.sub.3) δ ppm 2.31 (s, 3 H) 3.85 (s, 2 H) 4.81 (s, 2 H) 6.83-6.89 (m, 1 H) 6.90-6.99 (m, 3 H) 7.14-7.25 (m, 2 H) 26 .sup.1H NMR (CDCl.sub.3) δ ppm 3.93 (s, 2 H) 4.83 (s, 2 H) 6.89-7.06 (m, 4 H) 7.16-7.27 (m, 2 H) 7.30-7.37 (m, 1 H) 27 .sup.1H NMR (CDCl.sub.3) δ ppm 2.32 (s, 3 H) 3.80-3.84 (m, 2 H) 4.86 (s, 2 H) 6.97 (t, J = 8.06 Hz, 2 H) 7.12-7.27 (m, 5 H) 28 .sup.1H NMR (CDCl.sub.3) δ ppm 3.88 (s, 3 H) 4.00 (s, 2 H) 4.86 (s, 2 H) 6.91 (d, J = 8.25 Hz, 1 H) 6.98 (dt, J = 11.55, 8.02 Hz, 2 H) 7.17-7.30 (m, 3 H) 7.33 (t, J = 7.88 Hz, 1 H) 29 .sup.1H NMR (CDCl.sub.3) δ ppm 3.83 (s, 2 H) 5.34 (s, 2 H) 6.84 (br t, J = 8.61 Hz, 1 H) 7.02-7.15 (m, 2 H) 7.21 (br d, J = 7.06 Hz, 1 H) 7.42 (t, J = 7.65 Hz, 1 H) 7.54-7.64 (m, 2 H) 7.82-7.88 (m, 1 H) 7.91 (br d, J = 7.79 Hz, 1 H) 7.96 (br d, J = 7.97 Hz, 1 H) 30 .sup.1H NMR (CDCl.sub.3) δ ppm 3.88 (s, 2 H) 5.31 (s, 2 H) 6.80 (t, J = 8.66 Hz, 1 H) 6.99-7.13 (m, 2 H) 7.28 (d, J = 7.06 Hz, 1 H) 7.52 (dd, J = 8.57, 4.17 Hz, 1 H) 7.64 (t, J = 7.84 Hz, 1 H) 8.10 (d, J = 8.52 Hz, 1 H) 8.38 (d, J = 8.52 Hz, 1 H) 8.99 (br d, J = 3.94 Hz, 1 H) 31 .sup.1H NMR (CDCl.sub.3) δ ppm 2.54 (s, 3 H) 4.01 (s, 2 H) 4.99 (s, 2 H) 6.99-7.06 (m, 1 H) 7.20-7.32 (m, 2 H) 8.71 (s, 1 H) 32 .sup.1H NMR (CDCl.sub.3) δ ppm 4.09-4.14 (m, 2 H) 4.94 (s, 2 H) 7.00 (t, J = 8.39 Hz, 1 H) 7.08 (s, 1 H) 7.16-7.28 (m, 2 H) 7.65 (s, 1 H) 33 .sup.1H NMR (CDCl.sub.3) δ ppm 4.07 (s, 2 H) 5.04 (s, 2 H) 7.05 (t, J = 8.34 Hz, 1 H) 7.20-7.33 (m, 2 H) 7.80 (s, 1 H) 8.81 (s, 1 H) 34 .sup.1H NMR (CDCl.sub.3) δ ppm 4.21 (s, 2 H) 5.13 (s, 2 H) 7.02 (t, J = 8.20 Hz, 1 H) 7.16-7.28 (m, 2 H) 7.38 (d, J = 3.21 Hz, 1 H) 7.77 (d, J = 3.21 Hz, 1 H) 35 .sup.1H NMR (CDCl.sub.3) δ ppm 4.41-4.46 (m, 2 H) 5.92 (s, 2 H) 6.61 (d, J = 2.20 Hz, 1 H) 7.07 (t, J = 8.34 Hz, 1 H) 7.17-7.37 (m, 2 H) 7.74-7.83 (m, 1 H) 36 .sup.1H NMR (CDCl.sub.3) δ ppm 2.22 (s, 3 H) 2.38 (s, 3 H) 3.91 (s, 2 H) 4.62 (s, 2 H) 7.00 (t, J = 8.43, 1 H) 7.14-7.30 (m, 2 H) 37 .sup.1H NMR (CDCl.sub.3) δ ppm 4.04 (s, 2 H) 4.90 (s, 2 H) 6.93 (t, J = 8.44 Hz, 1 H) 7.09-7.27 (m, 2 H) 7.60-7.74 (m, 2 H) 8.53 (s, 1 H) 38 .sup.1H NMR (CDCl.sub.3) δ ppm 4.06 (s, 2 H) 4.80 (s, 2 H) 6.87-7.09 (m, 1 H) 7.13-7.29 (m, 2 H) 8.59 (m, 2 H) 9.17 (s, 1 H) 39 .sup.1H NMR (CDCl.sub.3) δ ppm 4.07 (s, 2 H) 5.02 (s, 2 H) 6.85-7.05 (m, 1 H) 7.12-7.26 (m, 3 H) 8.66 (d, J = 4.86 Hz, 2 H) 40 .sup.1H NMR (CDCl.sub.3) δ ppm 4.15 (s, 2 H) 4.89 (s, 2 H) 6.99-7.08 (m, 1 H) 7.12 (s, 1 H) 7.20-7.32 (m, 2 H) 7.87 (s, 1 H) 41 .sup.1H NMR (CDCl.sub.3) δ ppm 2.54 (s, 3 H) 4.15 (s, 2 H) 5.02 (s, 2 H) 7.00-7.07 (m, 1 H) 7.21-7.33 (m, 2 H) 42 .sup.1H NMR (CDCl.sub.3) δ ppm 3.98 (s, 2 H) 4.84 (s, 2 H) 6.97 (t, J = 8.52 Hz, 1 H) 7.14-7.27 (m, 2 H) 7.30 (dd, J = 7.74, 4.90 Hz, 1 H) 7.59 (br d, J = 7.88 Hz, 1 H) 8.49 (s, 1 H) 8.58 (br d, J = 3.94 Hz, 1 H) 43 .sup.1H NMR (CDCl.sub.3) δ ppm 3.96 (s, 2 H) 4.83 (s, 2 H) 6.93 (t, J = 8.66 Hz, 1 H) 7.06 (br d, J = 5.13 Hz, 2 H) 7.12-7.27 (m, 2 H) 8.56 (br d, J = 5.13 Hz, 2 H) 44 .sup.1H NMR (CDCl.sub.3) δ ppm 4.01 (s, 2 H) 4.68 (s, 2 H) 6.37 (s, 1 H) 6.98-7.07 (m, 1 H) 7.20-7.31 (m, 2 H) 7.42 (d, J = 1.19 Hz, 2 H) 45 .sup.1H NMR (CDCl.sub.3) δ ppm 4.06 (s, 2 H) 5.02 (s, 2 H) 6.96 (br t, J = 8.57 Hz, 1 H) 7.13-7.26 (m, 2 H) 8.52 (s, 2 H) 46 .sup.1H NMR (CDCl.sub.3) δ ppm 2.18 (s, 3 H) 3.79 (s, 3 H) 3.99 (s, 2 H) 4.81 (s, 2 H) 5.92 (s, 1 H) 7.00 (t, J = 8.52 Hz, 1 H) 7.17-7.27 (m, 2 H) 47 .sup.1H NMR (CDCl.sub.3) δ ppm 3.71 (s, 3 H) 4.28 (d, J = 1.01 Hz, 2 H) 4.92 (s, 2 H) 6.87 (s, 1 H) 6.93-7.01 (m, 2 H) 7.13-7.25 (m, 2 H) 48 .sup.1H NMR (CDCl.sub.3) δ ppm 1.91 (d, J = 7.24 Hz, 3 H) 3.63 (d, J = 16.77 Hz, 1 H) 3.88 (d, J = 16.77 Hz, 1 H) 5.32 (q, J = 7.15 Hz, 1 H) 6.94-7.02 (m, 1 H) 7.09 (t, J = 8.57 Hz, 2 H) 7.15-7.28 (m, 2 H) 7.36 (dd, J = 8.48, 5.27 Hz, 2 H) 49 .sup.1H NMR (CDCl.sub.3) δ ppm 1.93 (d, J = 7.24 Hz, 3 H) 3.56 (d, J = 16.86 Hz, 1 H) 3.84 (d, J = 16.86 Hz, 1 H) 5.39 (q, J = 7.15 Hz, 1 H) 6.93-7.01 (m, 1 H) 7.14-7.26 (m, 2 H) 7.34-7.46 (m, 5 H) 50 .sup.1H NMR (CDCl.sub.3) δ ppm 3.72-3.89 (m, 2 H) 4.69-4.81 (m, 2 H) 6.80 (d, J = 7.79 Hz, 1 H) 6.92 (t, J = 8.52 Hz, 2 H) 7.04-7.14 (br s, 3 H) 7.40 (d, J = 7.97 Hz, 1 H) 51 .sup.1H NMR (CDCl.sub.3) δ ppm 3.81 (s, 2 H) 4.70 (s, 2 H) 6.88-7.03 (m, 4 H) 7.08-7.15 (m, 3H) 52 .sup.1H NMR (CDCl.sub.3) δ ppm 3.83 (s, 2 H) 4.80 (s, 2 H) 6.87 (t, J = 8.48 Hz, 2 H) 7.01-7.10 (m, 3 H) 7.22-7.29 (m, 1 H) 7.63 (d, J = 7.79 Hz, 1 H) 53 .sup.1H NMR (CDCl.sub.3) δ ppm 3.87 (s, 2 H) 4.58 (s, 2 H) 6.77-6.89 (m, 2 H) 7.01 (t, J = 8.48 Hz, 2 H) 7.18 (dd, J = 8.20, 5.27 Hz, 2 H) 7.22-7.30 (m, 1 H) 54 .sup.1H NMR (CDCl.sub.3) δ ppm 3.77 (s, 2 H) 4.54 (s, 2 H) 6.98-7.06 (m, 4 H) 7.06-7.17 (m, 4 H) 55 .sup.1H NMR (CDCl.sub.3) δ ppm 3.91 (s, 2 H) 4.80 (s, 2 H) 6.96 (br t, J = 8.48 Hz, 1 H) 7.03 (br t, J = 8.52 Hz, 2 H) 7.17 (br t, J = 8.43 Hz, 1 H) 7.20-7.27 (m, 3 H) 56 .sup.1H NMR (CDCl.sub.3) δ ppm 4.00 (s, 2 H) 4.90 (s, 2 H) 6.95-7.02 (m, 1 H) 7.10 (t, J = 9.26 Hz, 1 H) 7.13-7.27 (m, 3 H) 7.28-7.39 (m, 2 H) 57 .sup.1H NMR (CDCl.sub.3) δ ppm 3.78 (s, 3 H) 3.90 (s, 2 H) 4.81 (s, 2 H) 6.77 (s, 1 H) 6.81 (d, J = 7.61 Hz, 1 H) 6.86 (dd, J = 8.25, 2.20 Hz, 1 H) 6.93-7.00 (m, 1 H) 7.13-7.18 (m, 1 H) 7.21 (dd, J = 8.02, 5.82 Hz, 1 H) 7.27 (t, J = 7.93 Hz, 1 H) 58 .sup.1H NMR (CDCl.sub.3) δ ppm 4.02 (s, 2 H) 4.97 (s, 2 H) 6.89 (br t, J = 8.57 Hz, 1 H) 7.06-7.22 (m, 3 H) 7.35 (t, J = 7.88 Hz, 1 H) 7.66 (br d, J = 7.70 Hz, 1 H) 59 .sup.1H NMR (CDCl.sub.3) δ ppm 3.97 (s, 2 H) 4.94 (s, 2 H) 6.89-6.96 (m, 2 H) 7.10-7.15 (m, 1 H) 7.15-7.22 (m, 2 H) 7.42 (d, J = 8.06 Hz, 1 H) 60 .sup.1H NMR (CDCl.sub.3) δ ppm 3.96 (s, 2 H) 4.90 (m, 2 H) 6.91-7.02 (m, 2 H) 7.09-7.23 (m, 4 H) 61 .sup.1H NMR (CDCl.sub.3) δ ppm 4.02 (s, 2 H) 4.85 (s, 2 H) 6.82-6.94 (m, 2 H) 6.96-7.04 (m, 1 H) 7.17-7.27 (m, 2 H) 7.31-7.39 (m, 1 H) 62 .sup.1H NMR (CDCl.sub.3) δ ppm 4.19 (s, 2 H) 4.92 (s, 2 H) 6.95-7.01 (m, 1 H) 7.15-7.27 (m, 3 H) 7.29 (d, J = 7.79 Hz, 1 H) 7.64-7.72 (m, 1 H) 8.54 (br d, J = 4.49 Hz, 1 H) 63 .sup.1H NMR (CDCl.sub.3) δ ppm 3.95 (s, 2 H) 4.90 (s, 2 H) 6.93 (t, J = 8.52 Hz, 1 H) 7.11-7.23 (m, 2 H) 7.32 (br d, J = 7.97 Hz, 2 H) 7.59 (d, J = 8.06 Hz, 2 H) 64 .sup.1H NMR (CDCl.sub.3) δ ppm 2.57 (s, 3 H) 4.00 (s, 2 H) 4.84 (s, 2 H) 6.83 (t, J = 8.85 Hz, 1 H) 7.02-7.14 (m, 2 H) 7.19 (d, J = 7.97 Hz, 1 H) 7.38 (d, J = 7.97 Hz, 1 H) 65 .sup.1H NMR (CDCl.sub.3) δ ppm 3.91 (s, 2 H) 4.79 (s, 2 H) 6.95 (m, 1 H) 7.10-7.26 (m, 4 H) 7.30-7.40 (m, 2 H) 66 .sup.1H NMR (CDCl.sub.3) δ ppm 4.16 (s, 2 H) 4.84 (s, 2 H) 6.49 (d, J = 3.30 Hz, 1 H) 6.65-6.87 (m, 1 H) 6.92-7.12 (t, J = 8.54 Hz, 1 H) 7.14-7.34 (m, 2 H) 67 .sup.1H NMR (CDCl.sub.3) δ ppm 2.22-2.44 (m, 3 H) 3.86-4.06 (m, 2 H) 4.73-4.91 (m, 2 H) 6.93-7.03 (m, 1 H) 7.12-7.28 (m, 6 H) 68 .sup.1H NMR (CDCl.sub.3) δ ppm 3.78 (s, 3 H) 3.90 (s, 2 H) 4.77 (s, 2 H) 6.87 (d, J = 8.52 Hz, 2 H) 6.96 (t, J = 8.66 Hz, 1 H) 7.13-7.25 (m, 4 H) 69 .sup.1H NMR (CDCl.sub.3) δ ppm 1.77-1.88 (m, 2 H) 1.88-2.01 (m, 2 H) 2.10 (br d, J = 5.13 Hz, 2 H) 2.63-2.74 (m, 1 H) 3.65 (br d, J = 7.37 Hz, 2 H) 4.03 (s, 2 H) 7.03-7.11 (m, 1 H) 7.23-7.36 (m, 2H) 70 .sup.1H NMR (CDCl.sub.3) δ ppm 1.38 (br t, J = 12.07 Hz, 2 H) 1.48 (br t, J = 12.07 Hz, 2 H) 1.68-1.88 (br s, 5 H) 3.48 (br d, J = 7.26 Hz, 2 H) 3.89-4.00 (m, 4 H) 4.03 (s, 2 H) 7.03-7.13 (m, 1 H) 7.21-7.38 (m, 2 H) 71 .sup.1H NMR (CDCl.sub.3) δ ppm 3.99 (s, 2 H) 4.65 (s, 2 H) 6.96-7.02 (m, 2 H) 7.04 (d, J = 6.97 Hz, 1 H) 7.09-7.17 (m, 3 H) 7.41 (dd, J = 8.02, 1.15 Hz, 1 H) 72 .sup.1H NMR (CDCl.sub.3) δ ppm 4.03 (s, 2 H) 4.68 (s, 2 H) 6.96 (t, J = 8.52 Hz, 2 H) 7.12 (dd, J = 8.34, 5.22 Hz, 2 H) 7.27-7.36 (m, 2 H) 7.65 (dd, J = 7.01, 1.97 Hz, 1 H) 73 .sup.1H NMR (CDCl.sub.3) δ ppm 3.91 (s, 2 H) 4.65 (s, 2 H) 6.94 (td, J = 8.20, 2.57 Hz, 1 H) 6.98-7.04 (m, 2 H) 7.10-7.18 (m, 4 H) 74 .sup.1H NMR (CDCl.sub.3) δ ppm 3.91 (s, 2 H) 4.64 (s, 2 H) 7.00 (br t, J = 8.48 Hz, 2 H) 7.07 (d, J = 8.34 Hz, 1 H) 7.10-7.16 (m, 2 H) 7.19 (dd, J = 8.25, 1.56 Hz, 1 H) 7.40 (s, 1 H) 75 .sup.1H NMR (CDCl.sub.3) δ ppm 3.84 (s, 2 H) 4.61 (s, 2 H) 6.94-7.00 (m, 2 H) 7.02-7.18 (m, 5 H) 7.24-7.33 (m, 1 H) 76 .sup.1H NMR (CDCl.sub.3) δ ppm 3.94 (s, 2 H) 4.61 (s, 2 H) 6.96 (t, J = 8.57 Hz, 2 H) 7.08-7.26 (m, 5 H) 7.37 (d, J = 7.79 Hz, 1 H) 77 .sup.1H NMR (CDCl.sub.3) δ ppm 1.73 (s, 3 H) 1.74 (s, 3 H) 4.36 (s, 2 H) 6.79 (m, 4 H) 6.86 (d, J = 7.97 Hz, 1 H) 6.91-7.00 (m, 1 H) 7.08 (td, J = 8.06, 5.59 Hz, 1 H) 78 .sup.1H NMR (CDCl.sub.3) δ ppm 1.63 (d, J = 6.96 Hz, 3 H) 4.30 (d, J = 16.13 Hz, 1 H) 4.33-4.41 (m, 1 H) 4.54 (d, J = 16.13 Hz, 1 H) 6.78-6.94 (m, 5 H) 7.12-7.17 (m, 2 H) 79 .sup.1H NMR (CDCl.sub.3) δ ppm 3.78 (s, 2 H) 4.56 (s, 2 H) 7.00-7.06 (m, 2 H) 7.07-7.17 (m, 4 H) 8.57-8.62 (m, 2 H) 80 .sup.1H NMR (CDCl.sub.3) δ ppm 3.80 (s, 2 H) 4.65 (s, 2 H) 6.76-6.88 (m, 2 H) 7.00 (br t, J = 8.39 Hz, 2 H) 7.10-7.19 (m, 3 H) 81 .sup.1H NMR (CDCl.sub.3) δ ppm 3.87 (s, 2 H) 4.84 (s, 2 H) 6.80 (br d, J = 9.26 Hz, 1 H) 6.85-7.00 (m, 3 H) 7.08-7.18 (m, 1 H) 7.18-7.29 (m, 2 H) 82 .sup.1H NMR (CDCl.sub.3) δ ppm 0.92-1.06 (m, 2 H) 1.12-1.30 (m, 3 H) 1.64-1.82 (m, 6 H) 3.43 (d, J = 7.15 Hz, 2 H) 4.04 (d, J = 0.82 Hz, 2 H) 7.01-7.11 (m, 1 H) 7.24-7.34 (m, 2 H) 83 .sup.1H NMR (CDCl.sub.3) δ ppm 0.39-0.46 (m, 2 H) 0.60-0.68 (m, 2 H) 1.05-1.14 (m, 1 H) 3.53 (br d, J = 7.05 Hz, 2 H) 4.10 (s, 2 H) 7.05-7.11 (m, 1 H) 7.25-7.35 (m, 2 H) 84 .sup.1H NMR (CDCl.sub.3) δ ppm 1.27-1.41 (m, 2 H) 1.58-1.87 (m, 5 H) 2.05-2.18 (m, 2 H) 3.49 (d, J = 7.33 Hz, 2 H) 4.03 (s, 2 H) 7.06 (t, J = 8.66 Hz, 1 H) 7.24-7.36 (m, 2 H) 85 .sup.1H NMR (CDCl.sub.3) δ ppm 1.24-1.31 (m, 2 H) 1.56-1.62 (m, 2 H) 1.65-1.72 (m, 2 H) 1.74-1.81 (m, 2 H) 2.26-2.30 (m, 1 H) 3.55 (d, J = 7.80 Hz, 2 H) 4.05 (s, 2 H) 7.05 (t, J = 8.70 Hz, 1 H) 7.24-7.30 (m, 2 H) 86 .sup.1H NMR (CDCl.sub.3) δ ppm 0.88 (d, J = 15.06 Hz, 6 H) 1.11-1.20 (m, 4 H) 1.41 (br d, J = 10.79 Hz, 2 H) 1.49-1.53 (m, 2 H) 1.62 (td, J = 7.34, 3.68 Hz, 1 H) 3.46 (d, J = 7.58 Hz, 2 H) 4.04 (s, 2 H) 7.05 (t, J = 8.46 Hz, 1 H) 7.26 (m, 2 H) 87 .sup.1H NMR (CDCl.sub.3) δ ppm 0.93-1.08 (m, 5 H) 1.12-1.31 (m, 3 H) 1.37-1.50 (m, 1 H) 1.57-1.80 (m, 4 H) 3.32 (dd, J = 14.30, 11.09 Hz, 1 H) 3.86 (dd, J = 14.30, 4.31 Hz, 1 H) 4.03 (s, 2 H) 7.03-7.11 (m, 1 H) 7.24-7.34 (m, 2 H) 88 .sup.1H NMR (CDCl.sub.3) δ ppm 0.81 (dd, J = 12.23, 5.27 Hz, 1 H) 1.09-1.25 (m, 2 H) 1.40-1.69 (m, 3 H) 1.72-1.82 (m, 1 H) 1.95-1.95 (m, 1 H) 2.16-2.33 (m, 2 H) 3.30-3.47 (m, 1 H) 3.63 (d, J = 7.70 Hz, 2 H) 4.06 (s, 2 H) 7.03-7.12 (m, 1 H) 7.23-7.36 (m, 2 H) 89 .sup.1H NMR (CDCl.sub.3) δ ppm 1.42 (dtd, J = 12.80, 8.59, 8.59, 3.94 Hz, 1 H) 1.56 (quind, J = 8.64, 8.64, 8.64, 8.64, 3.94 Hz, 1 H) 1.65-1.78 (m, 1 H) 1.79-1.88 (m, 1 H) 2.04 (dtq, J = 11.31, 7.68, 7.68, 3.88, 3.88, 3.88 Hz, 1 H) 3.35 (dd, J = 11.59, 7.38 Hz, 1 H) 3.49-3.65 (m, 3 H) 3.71-3.80 (m, 2 H) 4.00-4.13 (m, 2 H) 7.03-7.10 (m, 1 H) 7.23-7.34 (m, 2 H) 90 .sup.1H NMR (CDCl.sub.3) δ ppm 1.12 (t, J = 7.51 Hz, 3 H) 2.12-2.24(m, 2 H) 4.18-4.23 (m, 2 H) 4.40 (t, J = 2.20 Hz, 2 H) 7.05 (t, J = 8.23 Hz, 1 H) 7.20-7.34 (m, 2 H) 91 .sup.1H NMR (CDCl.sub.3) δ ppm 1.32-1.42 (m, 5 H) 1.49-1.62 (m, 3 H) 1.63-1.74 (m, 2 H) 2.26-2.32 (m, 1 H) 3.83 (s, 2 H) 4.03 (s, 2 H) 7.03-7.10 (m, 1 H) 7.23-7.34 (m, 2 H) 92 .sup.1H NMR (CDCl.sub.3) δ ppm 1.15-1.26 (m, 2 H) 1.36-1.64 (m, 7 H) 1.65-1.74 (m, 3 H) 1.88-2.00 (m, 1 H) 3.42 (d, J = 7.79 Hz, 2 H) 4.04 (s, 2 H) 7.03-7.10 (m, 1 H) 7.24-7.35 (m, 2 H) 93 .sup.1H NMR (CDCl.sub.3) δ ppm 1.35 (qd, J = 12.19, 4.31 Hz, 2 H) 1.57 (br d, J = 12.56 Hz, 2 H) 1.89-2.03 (m, 1 H) 3.32 (br t, J = 11.68 Hz, 2 H) 3.47 (d, J = 7.42 Hz, 2 H) 3.97 (br dd, J = 11.50, 3.71 Hz, 2 H) 4.04 (s, 2 H) 7.06 (t, J = 8.61 Hz, 1 H) 7.23-7.34 (m, 2 H) 94 .sup.1H NMR (CDCl.sub.3) δ ppm 1.21-1.34 (m, 1 H) 1.47-1.58 (m, 3 H) 1.67 (br d, J = 12.46 Hz, 1 H) 1.84-1.93 (m, 1 H) 3.33-3.44 (m, 1 H) 3.48-3.61 (m, 2 H) 3.69-3.77 (m, 1 H) 3.98 (br d, J = 10.72 Hz, 1 H) 4.06 (d, J = 16.95 Hz, 1 H) 4.32 (d, J = 16.86 Hz, 1 H) 6.99-7.07 (m, 1 H) 7.19-7.30 (m, 2 H) 95 .sup.1H NMR (CDCl.sub.3) δ ppm 1.78 (s, 3 H) 4.18 (s, 2 H) 4.36 (br d, J = 2.02 Hz, 2 H) 7.03 (t, J = 8.52 Hz, 1 H) 7.20-7.31 (m, 2 H) 96 .sup.1H NMR (CDCl.sub.3) δ ppm 1.57 (m, 3 H) 1.60-1.68 (m, 3 H) 1.91 (br s, 2 H) 2.01 (s, 2 H) 4.03 (s, 2 H) 4.14 (s, 2 H) 7.02-7.08 (m, 1 H) 7.23-7.32 (m, 2 H) 97 .sup.1H NMR (CDCl.sub.3) δ ppm 1.23-1.41 (m, 2 H) 1.52-1.67 (m, 2 H) 1.76-1.90 (m, 3 H) 2.10-2.24 (m, 1 H) 2.27-2.44 (m, 1 H) 3.61 (dd, J = 14.75, 6.51 Hz, 1 H) 3.94 (dd, J = 14.85, 7.06 Hz, 1 H) 3.98-4.06 (m, 1 H) 4.10-4.18 (m, 1 H) 7.03-7.10 (m, 1 H) 7.24-7.33 (m, 2 H) 98 .sup.1H NMR (CDCl.sub.3) δ ppm 3.32 (t, J = 11.23 Hz, 1 H) 3.52-3.62 (m, 2 H) 3.67-3.77 (m, 3 H) 3.78-3.91 (m, 3 H) 4.09-4.17 (m, 1 H) 4.19-4.28 (m, 1 H) 7.01-7.08 (m, 1 H) 7.22-7.31 (m, 2 H) 99 .sup.1H NMR (CDCl.sub.3) δ ppm 0.90 (s, 3 H) 1.06 (s, 3 H) 1.11-1.30 (m, 3 H) 1.34-1.45 (m, 2 H) 1.47-1.55 (m, 2 H) 1.56-1.65 (m, 1 H) 1.71-1.81 (m, 1 H) 3.35 (dd, J = 14.20, 11.46 Hz, 1 H) 3.78 (dd, J = 14.20, 3.44 Hz, 1 H) 4.02 (s, 2 H) 7.03-7.11 (m, 1 H) 7.25-7.35 (m, 2 H) 100 .sup.1H NMR (CDCl.sub.3) δ ppm 3.42 (s, 3 H) 4.14 (s, 2 H) 5.03 (s, 2 H) 7.02-7.10 (m, 1 H) 7.23-7.34 (m, 2 H) 101 .sup.1H NMR (CDCl.sub.3) δ ppm 1.18 (t, J = 6.92 Hz, 3 H) 3.58 (q, J = 6.97 Hz, 2 H) 4.14 (s, 2 H) 5.05 (s, 2 H) 7.03 (t, J = 8.57 Hz, 1 H) 7.19-7.30 (m, 2 H) 102 .sup.1H NMR (CDCl.sub.3) δ ppm 0.91 (t, J = 7.42 Hz, 3 H) 1.58 (sxt, J = 7.07 Hz, 2 H) 3.50 (t, J = 6.51 Hz, 2 H) 4.15 (d, J = 1.10 Hz, 2 H) 5.08 (s, 2 H) 7.00-7.10 (m, 1 H) 7.22-7.33 (m, 2 H) 104 .sup.1H NMR (CDCl.sub.3) δ ppm 4.00 (s, 2 H) 4.76 (s, 2 H) 6.96-7.05 (m, 2 H) 7.17-7.28 (m, 4 H) 7.64-7.71 (m, 1 H) 8.51-8.57 (m, 1 H) 105 .sup.1H NMR (CDCl.sub.3) δ ppm 4.03 (s, 2 H) 4.61 (s, 2 H) 6.93 (t, J = 8.08 Hz, 2 H) 7.05-7.26 (m, 3 H) 7.41 (br t, J = 5.82 Hz, 2 H) 7.67 (d, J = 6.64 Hz, 1 H) 107 .sup.1H NMR (CDCl.sub.3) δ ppm 3.79 (s, 2 H) 4.54 (s, 2 H) 6.84 (br d, J = 9.26 Hz, 1 H) 6.91-7.02 (m, 4 H) 7.04-7.10 (m, 2 H) 7.28 (td, J = 7.93, 6.05 Hz, 1H) 108 .sup.1H NMR (CDCl.sub.3) δ ppm 3.79 (s, 2 H) 4.49 (s, 2 H) 6.96-7.02 (m, 3 H) 7.03-7.10 (m, 2 H) 7.14-7.19 (m, 2 H) 7.31-7.37 (m, 2 H) 109 .sup.1H NMR (CDCl.sub.3) δ ppm 3.76 (m, 5 H) 4.50 (s, 2 H) 6.66 (s, 1 H) 6.73 (d, J = 7.51 Hz, 1 H) 6.82 (dd, J = 8.25, 1.83 Hz, 1 H) 6.93-7.01 (m, 2 H) 7.03-7.10 (m, 2 H) 7.24 (t, J = 7.88 Hz, 1 H) 110 .sup.1H NMR (CDCl.sub.3) δ ppm 0.88 (br d, J = 9.40 Hz, 2 H) 1.10 (br s, 3 H) 1.48-1.64 (m, 4 H) 1.64-1.70 (m, 2 H) 3.33 (br d, J = 7.37 Hz, 2 H) 4.10 (s, 2 H) 7.23-7.31 (m, 2 H) 7.69 (br t, J = 7.58 Hz, 1 H) 8.54 (br d, J = 4.06 Hz, 1 H) 111 .sup.1H NMR (CDCl.sub.3) δ ppm 0.88 (br d, J = 11.11 Hz, 2 H) 1.12 (m, 3 H) 1.57 (br d, J = 12.60 Hz, 3 H) 1.65 (m, 1 H) 1.68-1.80 (m, 2 H) 3.21 (d, J = 7.26 Hz, 2 H) 3.92 (s, 2 H) 7.21 (d, J = 4.49 Hz, 2 H) 8.61-8.71 (d, J = 4.49 Hz, 2 H) 112 .sup.1H NMR (CDCl.sub.3) δ ppm 0.78-0.91 (m, 2H) 1.01-1.15 (m, 3 H) 1.35-1.46 (m, 1 H) 1.53 (br d, J = 12.56 Hz, 2 H) 1.58-1.70 (m, 3 H) 3.16 (d, J = 7.42 Hz, 2 H) 3.74-3.80 (m, 3 H) 3.84 (s, 2 H) 6.87 (d, J = 8.61 Hz, 2 H) 7.14 (d, J = 8.61 Hz, 2 H) 113 .sup.1H NMR (CDCl.sub.3) δ ppm 0.84-0.98 (m, 2 H) 1.10 (br s, 3 H) 1.48-1.75 (m, 6 H) 3.30 (d, J = 7.42 Hz, 2 H) 4.12 (s, 2 H) 7.37-7.43 (m, 1 H) 7.50 (br d, J = 7.70 Hz, 1 H) 7.71 (d, J = 7.79 Hz, 1 H) 114 .sup.1H NMR (CDCl.sub.3) δ ppm 0.83-0.95 (m, 2H) 1.03-1.15 (m, 3 H) 1.52-1.71 (m, 6 H) 3.26 (d, J = 7.15 Hz, 2 H) 3.98 (s, 2 H) 6.97 (td, J = 8.23, 2.61 Hz, 1 H) 7.14 (dd, J = 8.34, 2.57 Hz, 1 H) 7.25 (dd, J = 8.57, 5.91 Hz, 1 H) 115 .sup.1H NMR (CDCl.sub.3) δ ppm 0.80-0.98 (m, 2 H) 1.06-1.20 (m, 3 H) 1.44-1.81 (m, 6 H) 3.27 (d, J = 7.42 Hz, 2 H) 4.09 (s, 2 H) 7.15-7.29 (m, 2 H) 7.47 (dd, J = 7.65, 1.60 Hz, 1 H) 116 .sup.1H NMR (CDCl.sub.3) δ ppm 0.80-0.92 (m, 2H) 1.01-1.13 (m, 3 H) 1.39-1.49 (m, 1 H) 1.54 (br d, J = 12.37 Hz, 2 H) 1.60-1.72 (m, 3 H) 3.21 (d, J = 7.51 Hz, 2 H) 4.10 (s, 2 H) 7.33 (d, J = 7.70 Hz, 1 H) 7.42-7.49 (m, 1 H) 7.53-7.59 (m, 1 H) 7.73 (d, J = 7.70 Hz, 1 H) 117 .sup.1H NMR (CDCl.sub.3) δ ppm 0.82-0.97 (m, 2 H) 1.10 (br s, 3 H) 1.44-1.77 (m, 6 H) 3.25 (d, J = 7.42 Hz, 2 H) 4.06 (s, 2 H) 7.24-7.31 (m, 3 H) 7.41-7.46 (m, 1 H) 118 .sup.1H NMR (CDCl.sub.3) δ ppm 0.84-1.00 (m, 2 H) 1.08-1.21 (m, 3 H) 1.50-1.78 (m, 6 H) 3.27 (d, J = 7.15 Hz, 2 H) 4.01 (s, 2 H) 7.15-7.32 (m, 2 H) 7.46 (d, J = 1.47 Hz, 1 H) 119 .sup.1H NMR (CDCl.sub.3) δ ppm 0.81-0.96 (m, 2H) 1.04-1.18 (m, 3 H) 1.48-1.74 (m, 6 H) 3.26 (d, J = 7.24 Hz, 2 H) 3.87 (s, 2 H) 6.77-6.92 (m, 2 H) 7.18-7.28 (m, 1 H) 120 .sup.1H NMR (CDCl.sub.3) δ ppm 0.78-0.93 (m, 2 H) 1.08 (br s, 3 H) 1.40-1.51 (m, 1 H) 1.52-1.70 (m, 5 H) 3.23 (d, J = 7.33 Hz, 2 H) 3.91 (s, 2 H) 7.02-7.14 (m, 2 H) 7.20-7.25 (m, 1 H) 7.25-7.33 (m, 1 H) 121 .sup.1H NMR (CDCl.sub.3) δ ppm 0.61-0.76 (m, 2 H) 0.86-1.09 (m, 4 H) 1.33 (br d, J = 11.73 Hz, 2 H) 1.49-1.75 (m, 3 H) 1.90 (d, J = 4.67 Hz, 6 H) 3.03 (d, J = 7.70 Hz, 2 H) 7.06 (ddd, J = 13.01, 8.11, 1.51 Hz, 1 H) 7.16-7.32 (m, 2 H) 122 .sup.1H NMR (CDCl.sub.3) δ ppm 0.67-0.79 (m, 1 H) 0.85 (qd, J = 12.04, 3.39 Hz, 1 H) 0.99-1.10 (m, 3 H) 1.22-1.31 (m, 2 H) 1.39-1.49 (m, 2 H) 1.59-1.67 (m, 2 H) 1.70 (d, J = 7.06 Hz, 3 H) 2.78 (dd, J = 14.39, 7.70 Hz, 1 H) 3.22 (dd, J = 14.39, 7.51 Hz, 1 H) 4.54 (q, J = 6.90 Hz, 1 H) 7.00-7.08 (m, 1 H) 7.24-7.34 (m, 2 H) 123 .sup.1H NMR (CDCl.sub.3) δ ppm 0.80-0.94 (m, 2 H) 1.01-1.18 (m, 3 H) 1.45-1.75 (m, 6 H) 3.23 (d, J = 7.24 Hz, 2 H) 3.91 (s, 2 H) 7.31 (dd, J = 7.79, 4.67 Hz, 1 H) 7.60 (br d, J = 7.88 Hz, 1 H) 8.54 (d, J = 1.56 Hz, 1 H) 8.57 (d, J = 4.67 Hz, 1 H) 125 .sup.1H NMR (CDCl.sub.3) δ ppm 0.80-0.92 (m, 2 H) 1.09 (br s, 3 H) 1.45 (ddt, J = 14.95, 7.48, 3.68, 3.68 Hz, 1 H) 1.55 (br d, J = 12.37 Hz, 2 H) 1.60-1.74 (m, 3 H) 3.19 (d, J = 7.42 Hz, 2 H) 3.91 (s, 2 H) 6.92-7.08 (m, 3 H) 7.34 (td, J = 7.90, 6.00 Hz, 1 H) 126 .sup.1H NMR (CDCl.sub.3) δ ppm 0.77-0.91 (m, 2 H) 1.00-1.16 (m, 3 H) 1.41 (ddtd, J = 14.98, 11.24, 7.44, 7.44, 3.44 Hz, 1 H) 1.53 (br d, J = 12.46 Hz, 2 H) 1.58-1.72 (m, 3 H) 3.17 (d, J = 7.42 Hz, 2 H) 3.91 (s, 2 H) 7.24 (br d, J = 6.78 Hz, 2 H) 7.29-7.40 (m, 3 H) 127 .sup.1H NMR (CDCl.sub.3) δ ppm 0.81-0.94 (m, 2 H) 1.03-1.16 (m, 3 H) 1.43 (dtt, J = 15.04, 7.49, 7.49, 3.87, 3.87 Hz, 1 H) 1.55 (br d, J = 12.37 Hz, 2 H) 1.60-1.74 (m, 3 H) 3.19 (d, J = 7.42 Hz, 2 H) 3.80 (s, 3 H) 3.89 (s, 2 H) 6.78 (s, 1 H) 6.81-6.91 (m, 2 H) 7.23-7.33 (m, 1 H) 128 .sup.1H NMR (CDCl.sub.3) δ ppm 1.55 (dq, J = 12.72, 9.05 Hz, 1 H) 1.78-1.88 (m, 1 H) 1.90-2.09 (m, 2 H) 2.12-2.30 (m, 2 H) 2.49 (dt, J = 15.95, 8.16 Hz, 1 H) 3.60 (d, J = 7.61 Hz, 2 H) 4.03 (s, 2 H) 6.96-7.12 (m, 1 H) 7.18-7.33 (m, 2 H) 129 .sup.1H NMR (CDCl.sub.3) δ ppm 0.78-1.02 (m, 4H) 1.02-1.24 (m, 6H) 1.52-1.62 (m, 4H) 1.62-1.76 (m, 8 H) 2.32 (d, J = 6.78 Hz, 2H) 3.28 (d, J = 7.51 Hz, 2H) 130 .sup.1H NMR (CDCl.sub.3) δ ppm 0.77-0.91 (m, 2 H) 0.97-1.16 (m, 3 H) 1.36 (ddd, J = 10.72, 7.33, 3.30 Hz, 1 H) 1.51-1.66 (m, 5 H) 2.24 (d, J = 7.24 Hz, 2 H) 4.89 (s, 2 H) 7.00 (t, J = 8.98 Hz, 1 H) 7.19 (d, J = 8.46 Hz, 1 H) 7.24-7.32 (m, 1 H) 131 .sup.1H NMR (CDCl.sub.3) δ ppm 0.81-0.94 (m, 2 H) 1.01-1.14 (m, 3 H) 1.48 (ddd, J = 10.52, 7.22, 3.25 Hz, 1 H) 1.53-1.71 (m, 5 H) 2.27 (d, J = 7.15 Hz, 2 H) 4.69 (s, 2 H) 6.96-7.04 (m, 2 H) 7.21 (dd, J = 8.11, 5.36 Hz, 2 H) 132 .sup.1H NMR (CDCl.sub.3) δ ppm 1.19-1.32 (m, 2 H) 1.52-1.73 (m, 3 H) 1.79 (br d, J = 13.20 Hz, 2 H) 1.97-2.10 (m, 2 H) 2.35 (d, J = 7.06 Hz, 2 H) 4.95 (s, 2 H) 7.07 (t, J = 8.89 Hz, 1 H) 7.27 (d, J = 8.16 Hz, 1 H) 7.31-7.40 (m, 1 H) 133 .sup.1H NMR (CDCl.sub.3) δ ppm 0.89-1.00 (m, 2 H) 1.11-1.27 (m, 4 H) 1.32-1.45 (m, 2 H) 1.59-1.84 (m, 8 H) 1.88-2.00 (m, 2 H) 2.03-2.16 (m, 2 H) 2.44 (d, J = 6.60 Hz, 2 H) 3.33 (d, J = 7.42 Hz, 2 H) 134 .sup.1H NMR (CDCl.sub.3) δ ppm 1.20-1.34 (m, 2 H) 1.53-1.73 (m, 3 H) 1.79 (br d, J = 13.29 Hz, 2 H) 1.97-2.10 (m, 2 H) 2.35 (d, J = 6.96 Hz, 2 H) 4.71 (s, 2 H) 7.06 (t, J = 8.39 Hz, 2 H) 7.20-7.27 (m, 2 H) 135 .sup.1H NMR (DMSO-d6) δ ppm 5.07-5.15 (m, 1 H) 5.19-5.27 (m, 1 H) 5.87 (br s, 1 H) 7.19 (br s, OH) 7.27 (t, J = 9.16 Hz, 1 H) 7.36-7.41 (m, 1 H) 7.41-7.50 (m, 1 H) 7.59-7.67 (m, 1 H) 7.85 (d, J = 7.70 Hz, 1 H) 7.95 (d, J = 7.79 Hz, 1 H) 136 .sup.1H NMR (DMSO-d.sub.6) δ ppm 4.88-4.96 (m, 1 H) 5.02-5.09 (m, 1 H) 5.96 (br s, 1 H) 7.27-7.40 (m, 6 H) 7.61 (t, J = 7.78 Hz, 1 H) 7.83 (br d, J = 7.63 Hz, 1 H) 7.99 (br d, J = 7.83 Hz, 1 H) 137 .sup.1H NMR (DMSO-d.sub.6) δ ppm 4.99-5.06 (m, 1 H) 5.10-5.18 (m, 1 H) 5.89 (br d, J = 5.22 Hz, 1 H) 6.98 (br d, J = 5.22 Hz, OH) 7.08 (br t, J = 8.48 Hz, 1 H) 7.14-7.24 (m, 2 H) 7.30-7.35 (m, 1 H) 7.36-7.44 (m, 1 H) 7.52-7.62 (m, 1 H) 138 .sup.1H NMR (DMSO-d.sub.6) δ ppm 5.06-5.14 (m, 1 H) 5.20-5.27 (m, 1 H) 5.81 (br s, 1 H) 7.16 (br s, OH) 7.24-7.32 (m, 1 H) 7.41 (t, J = 8.61 Hz, 1 H) 7.44-7.50 (m, 2 H) 7.64 (d, J = 7.82 Hz, 2 H) 139 .sup.1H NMR (CDCl.sub.3) δ ppm 3.95 (s, 2 H) 5.05 (s, 2 H) 6.98-7.03 (m, 1 H) 7.07 (t, J = 8.61 Hz, 2 H) 7.18-7.24 (m, 2 H) 7.27 (dd, J = 8.43, 5.32 Hz, 2 H) 140 .sup.1H NMR (CDCl.sub.3) δ ppm 1.01-1.15 (m, 2 H) 1.16-1.32 (m, 3 H) 1.66-1.82 (m, 5 H) 1.83-1.91 (m, 1 H) 3.69 (d, J = 7.61 Hz, 2 H) 4.07 (d, J = 1.19 Hz, 2 H) 7.02-7.10 (m, 1 H) 7.23-7.32 (br s, 2 H) 141 .sup.1H NMR (CDCl.sub.3) δ ppm 1.39-1.53 (m, 2 H) 1.62-1.86 (m, 4 H) 1.92-2.04 (m, 1 H) 2.10-2.22 (m, 2 H) 3.75 (d, J = 7.51 Hz, 2 H) 4.06 (s, 2 H) 7.04-7.11 (m, 1 H) 7.24-7.33 (m, 2H) 142 .sup.1H NMR (CDCl.sub.3) δ ppm 0.84-0.98 (m, 2 H) 1.09-1.33 (m, 4 H) 1.44-1.54 (q, J = 15.12, J = 6.87, 2 H) 1.61-1.75 (m, 5 H) 3.57-3.66 (t, 6.87, 2 H) 4.04 (s, 2 H) 7.02-7.10 (m, 1 H) 7.22-7.34 (m, 2 H) 143 .sup.1H NMR (CDCl.sub.3) δ ppm 1.44 (br d, J = 4.86 Hz, 2 H) 1.58 (quin, J = 5.50 Hz, 4 H) 2.45 (br s, 4 H) 2.58 (t, J = 5.64 Hz, 2 H) 3.71 (t, J = 5.64 Hz, 2 H) 4.19 (s, 2 H) 7.06 (br d, J = 8.06 Hz, 1 H) 7.17-7.35 (m, 2 H) 144 .sup.1H NMR (CDCl.sub.3) δ ppm 2.77 (t, J = 7.65 Hz, 2 H) 3.11 (t, J = 7.65 Hz, 2 H) 4.94 (s, 2 H) 6.90-7.12 (m, 3 H) 7.13-7.35 (m, 3 H) 145 .sup.1H NMR (CDCl.sub.3) δ ppm 2.70 (t, J = 7.93 Hz, 2 H) 3.11 (t, J = 7.93 Hz, 2 H) 4.71 (s, 2 H) 6.94-7.10 (m, 3 H) 7.13-7.31 (m, 4 H) 146 .sup.1H NMR (CDCl.sub.3) δ ppm 0.83-1.05 (m, 2 H) 1.06-1.28 (m, 3 H) 1.58-1.78 (m, 6 H) 2.70-2.84 (m, 2 H) 3.09-3.28 (m, 2 H) 3.35 (d, J = 7.42 Hz, 2 H) 7.00 (ddd, J = 9.23, 5.98, 3.39 Hz, 1 H) 7.15-7.27 (m, 2 H) 147 .sup.1H NMR (CDCl.sub.3) δ ppm 1.26-1.40 (m, 2 H) 1.58-1.79 (m, 4 H) 1.82-1.95 (m, 1 H) 2.05-2.17 (m, 2 H) 2.72-2.81 (m, 2 H) 3.21 (t, J = 7.42 Hz, 2 H) 3.43 (d, J = 7.42 Hz, 2 H) 6.98-7.06 (m, 1 H) 7.18-7.24 (m, 2 H) 148 .sup.1H NMR (CDCl.sub.3) δ ppm 1.55 (dq, J = 12.72, 9.05 Hz, 1 H) 1.78-1.88 (m, 1 H) 1.90-2.09 (m, 2 H) 2.12-2.30 (m, 2 H) 2.49 (dt, J = 15.95, 8.16 Hz, 1 H) 3.60 (d, J = 7.61 Hz, 2 H) 4.03 (s, 2 H) 6.96-7.12 (m, 1 H) 7.18-7.33 (m, 2 H) 149 .sup.1H NMR (CDCl.sub.3) δ ppm 1.55 (dq, J = 12.72, 9.05 Hz, 1 H) 1.78-1.88 (m, 1 H) 1.90-2.09 (m, 2 H) 2.12-2.30 (m, 2 H) 2.49 (dt, J = 15.95, 8.16 Hz, 1 H) 3.60 (d, J = 7.61 Hz, 2 H) 4.03 (s, 2 H) 6.96-7.12 (m, 1 H) 7.18-7.33 (m, 2 H) 150 .sup.1H NMR (CDCl.sub.3) δ 1.13-1.29 (m, 2H), 1.44-1.67 (m, 5H), 1.95-2.10 (m, 2H), 3.32 (d, J = 7.3 Hz, 2H), 3.93 (s, 2H), 7.05-7.19 (m, 2H), 7.21-7.38 (m, 2H). 151 .sup.1H NMR (CDCl.sub.3) δ 1.10-1.29 (m, 2H), 1.54 (m, 5H), 2.02 (m, 2H), 3.27 (d, J = 7.4 Hz, 2H), 3.92 (s, 2H), 6.98 (dt, J = 9.3, 2.1 Hz, 1H), 7.04 (td, J = 8.4, 2.5 Hz, 2H), 7.35 (td, J = 8.0, 5.9 Hz, 1H). 152 .sup.1H NMR (CDCl.sub.3) δ 1.11-1.29 (m, 2H), 1.46-1.71 (m, 5H), 2.04 (m, 2H), 3.26 (d, J = 7.0 Hz, 2H), 3.89 (s, 2H), 7.07 (t, J = 8.5 Hz, 2H), 7.19-7.27 (m, 2H). 153 .sup.1H NMR (CDCl.sub.3) δ 1.17-1.37 (m, 2H), 1.49-1.77 (m, 5H), 1.98-2.14 (m, 2H), 3.34 (d, J = 7.1 Hz, 2H), 3.88 (s, 2H), 6.82-6.94 (m, 2H), 7.20-7.30 (m, 1H). 154 .sup.1H NMR (CDCl.sub.3) δ 1.08-1.26 (m, 2H), 1.42-1.63 (m, 5H), 2.01 (m, 2H), 3.24 (d, J = 7.4 Hz, 2H), 3.79 (s, 3H), 3.85 (s, 2H), 6.86-6.91 (m, 2H), 7.12-7.17 (m, 2H). 155 .sup.1H NMR (CDCl.sub.3) δ 1.19-1.34 (m, 2H), 1.47-1.72 (m, 5H), 2.07 (m, 2H), 3.38 (d, J = 7.1 Hz, 2H), 4.13 (s, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.53 (dd, J = 7.8, 1.8 Hz, 1H), 7.70-7.78 (m, 1H). 156 .sup.1H NMR (CDCl.sub.3) δ 1.27 (m, 2H), 1.48-1.72 (m, 5H), 2.06 (m, 2H), 3.35 (d, J = 7.2 Hz, 2H), 4.08 (s, 2H), 7.13-7.28 (m, 2H), 7.47 (dd, J = 7.7, 1.9 Hz, 1H). 157 .sup.1H NMR (CDCl.sub.3) δ 1.22 (m, 2H), 1.43-1.70 (m, 5H), 2.05 (m, 2H), 3.29 (d, J = 7.3 Hz, 2H), 4.10 (s, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.52-7.62 (m, 1H), 7.74 (dd, J = 7.7, 1.5 Hz, 1H). 158 .sup.1H NMR (CDCl.sub.3) δ 1.23 (m, 2H), 1.44-1.73 (m, 5H), 2.04 (m, 2H), 3.32 (d, J = 7.3 Hz, 2H), 4.06 (s, 2H), 7.25-7.35 (m, 3H), 7.41-7.47 (m, 1H). 159 .sup.1H NMR (CDCl.sub.3) δ 1.21-1.36 (m, 2H), 1.51-1.78 (m, 5H), 2.01-2.15 (m, 2H), 3.34 (d, J = 7.2 Hz, 2H), 4.01 (s, 2H), 7.19-7.34 (m, 2H), 7.47 (s, 1H). 160 .sup.1H NMR (CDCl.sub.3) δ 1.08-1.23 (m, 2H), 1.31-1.49 (m, 2H), 1.50-1.60 (m, 3H), 1.99 (m, 2H), 3.25 (d, J = 7.4 Hz, 2H), 3.77 (s, 3H), 3.88 (s, 2H), 6.74-6.89 (m, 3H), 7.27 (t, J = 7.9 Hz, 1H). 161 .sup.1H NMR (CDCl.sub.3) δ 1.07-1.23 (m, 2H), 1.30-1.59 (m, 5H), 1.91-2.05 (m, 2H), 3.25 (d, J = 7.4 Hz, 2H), 3.92 (s, 2H), 7.21-7.27 (m, 2H), 7.30-7.40 (m, 3H). 162 .sup.1H NMR (CDCl.sub.3) δ 1.20-1.41 (m, 2H), 1.47-1.78 (m, 5H), 2.07 (m, 2H), 3.26-3.38 (d, J = 7.4 Hz, 2H), 4.00 (s, 2H), 7.02 (td, J = 8.2, 2.6 Hz, 1H), 7.20 (dd, J = 8.2, 2.6 Hz, 1H), 7.25-7.32 (m, 1H). 163 .sup.1H NMR (CDCl.sub.3) δ 0.80-0.99 (m, 2H), 1.06-1.20 (m, 3H), 1.49 (m, 1H), 1.57-1.76 (m, 5H), 1.86 (d, J = 7.2 Hz, 3H), 2.22 (dd, J = 15.6, 7.2 Hz, 1H), 2.29 (dd, J = 15.6, 7.2 Hz, 1H), 5.13 (q, J = 7.3 Hz, 1H), 7.02-7.13 (m, 2H), 7.29-7.39 (m, 2H). 164 .sup.1H NMR (CDCl.sub.3) δ 1.10-1.32 (m, 3H), 1.51-1.76 (m, 4H), 1.85 (s, 3H), 2.02 (m, 2H), 2.22 (dd, J = 16.1, 7.0 Hz, 1H), 2.33 (dd, J = 16.1, 7.0 Hz, 1H), 5.17 (q, J = 7.2 Hz, 1H), 7.04-7.13 (m, 2H), 7.28-7.36 (m, 2H). 165 .sup.1H NMR (CDCl.sub.3) δ 1.22-1.38 (m, 2H), 1.53-1.75 (m, 3H), 1.81 (ddq, J = 13.6, 5.1, 2.4 Hz, 2H), 2.04 (dddd, J = 13.8, 10.5, 7.0, 3.6 Hz, 2H), 2.43 (d, J = 7.0 Hz, 2H), 4.79 (s, 2H), 7.10 (ddd, J = 9.8, 8.4, 1.3 Hz, 1H), 7.16 (td, J = 7.5, 1.2 Hz, 1H), 7.30-7.40 (m, 2H). 166 .sup.1H NMR (CDCl.sub.3) δ 1.15-1.37 (m, 2H), 1.52-1.87 (m, 5H), 2.03 (tdt, J = 12.8, 5.3, 2.5 Hz, 2H), 2.35 (d, J = 6.9 Hz, 2H), 4.81 (s, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H). 167 .sup.1H NMR (CDCl.sub.3) δ 1.23-1.37 (m, 2H), 1.62 (m, 3H), 1.81 (m, 2H), 2.04 (tdt, J = 12.0, 7.0, 2.8 Hz, 2H), 2.39 (d, J = 7.0 Hz, 2H), 4.95 (s, 2H), 7.37 (dd, J = 7.3, 1.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.72-7.77 (m, 1H). 168 .sup.1H NMR (CDCl.sub.3) δ 1.31-1.47 (m, 2H), 1.71 (m, 2H), 1.89 (m, 3H), 2.08 (m, 2H), 2.57 (d, J = 6.6 Hz, 2H), 4.75 (s, 2H), 6.53 (d, J = 3.4 Hz, 1H), 6.79 (d, J = 3.2, 1H). 169 .sup.1H NMR (CDCl.sub.3) δ 1.26-1.40 (m, 2H), 1.58-1.79 (m, 2H), 1.84 (m, 3H), 1.98-2.11 (m, 2H), 2.40 (s, 3H), 2.50 (d, J = 6.6 Hz, 2H), 4.72 (s, 2H), 6.05 (s, 1H). 170 .sup.1H NMR (CDCl.sub.3) δ 1.18-1.33 (m, 2H), 1.47-1.69 (m, 3H), 1.77 (dtt, J = 13.2, 5.1, 2.5 Hz, 2H), 1.93-2.06 (m, 2H), 2.36 (d, J = 7.1 Hz, 2H), 4.88 (s, 2H), 7.13-7.21 (m, 1H), 7.29 (tt, J = 7.6, 5.5 Hz, 2H), 7.37-7.45 (m, 1H). 171 .sup.1H NMR (CDCl.sub.3) δ 1.18-1.31 (m, 2H), 1.51-1.71 (m, 3H), 1.76 (d, J = 13.3 Hz, 2H), 2.02 (m, 2H), 2.25-2.29 (m, 2H), 2.31 (s, 3H), 4.72 (s, 2H), 6.84-7.00 (m, 3H). 172 .sup.1H NMR (CDCl.sub.3) δ 1.05-1.22 (m, 2H), 1.65 (m, 5H), 1.78 (d, J = 6.9 Hz, 2H), 2.00 (m, 2H), 2.99 (t, J = 6.5 Hz, 2H), 3.74 (t, J = 6.5 Hz, 2H), 7.05-7.16 (m, 2H), 7.24-7.37 (m, 3H). 173 .sup.1H NMR (CDCl.sub.3) δ 1.80 (m, 2H), 1.93-2.00 (m, 2H), 2.04-2.13 (m, 2H), 2.21 (tdt, J = 9.8, 6.8, 3.7 Hz, 1H), 3.56 (d, J = 7.5 Hz, 2H), 4.04 (s, 2H), 7.05 (dd, J = 9.6, 8.1 Hz, 1H), 7.21-7.34 (m, 2H). 174 .sup.1H NMR (CDCl.sub.3) δ 3.21 (s, 3H), 4.04 (s, 2H), 7.04 (ddd, J = 9.5, 7.9, 1.6 Hz, 1H), 7.20-7.33 (m, 2H). 175 .sup.1H NMR (CDCl.sub.3) δ 1.25 (t, J = 7.3 Hz, 3H), 3.67 (q, J = 7.3 Hz, 2H), 4.05 (s, 2H), 7.05 (ddd, J = 9.3, 7.9, 1.6 Hz, 1H), 7.21-7.34 (m, 2H). 176 .sup.1H NMR (CDCl.sub.3) δ 0.94 (t, J = 7.5 Hz, 3H), 1.67 (dt, J = 14.9, 7.5 Hz, 2H), 3.51-3.60 (t, J = 7.5 Hz 2H), 4.03 (d, J = 1.5 Hz, 2H), 7.04 (m, 1H), 7.20-7.33 (m, 2H). 177 .sup.1H NMR (CDCl.sub.3) δ 0.91 (t, J = 7.4 Hz, 3H), 1.34 (h, J = 7.4 Hz, 2H), 1.52-1.65 (m, 2H), 3.58 (t, J = 7.6 Hz, 2H), 4.03 (s, 2H), 7.03 (m, 1H), 7.19-7.33 (m, 2H). 178 .sup.1H NMR (CDCl.sub.3) δ 0.98 (d, J = 6.7 Hz, 7H), 2.10 (dt, J = 13.5, 6.8 Hz, 1H), 3.42 (d, J = 7.7 Hz, 2H), 4.03 (s, 2H), 7.06 (m, 1H), 7.22-7.35 (m, 2H). 179 .sup.1H NMR (CDCl.sub.3) δ 0.78-0.92 (m, 2H), 1.07-1.27 (m, 6H), 1.64 (ddt, J = 15.5, 12.0, 5.4 Hz, 7H), 3.55 (t, J = 7.6 Hz, 2H), 4.04 (s, 2H), 7.01-7.08 (m, 1H).7.21-7.32 (m, 2H). 180 .sup.1H NMR (CDCl.sub.3) δ 1.40 (m, 2H), 1.55 (m, 4H), 1.90 (m, 2H), 2.38 (m, 6H), 3.68 (t, J = 6.8 Hz, 2H), 4.09 (s, 2H), 7.01 (ddd, J = 9.4, 7.9, 1.7 Hz, 1H), 7.17-7.31 (m, 2H). 181 .sup.1H NMR (CDCl.sub.3) δ 1.99 (tt, J = 13.8, 5.7 Hz, 4H), 2.62 (t, J = 5.7 Hz, 4H), 2.67 (t, J = 5.8 Hz, 2H), 3.70 (t, J = 5.8 Hz, 2H), 4.12 (d, J = 1.6 Hz, 2H), 7.07 (m, 1H), 7.23-7.35 (m, 2H). 182 .sup.1H NMR (CDCl.sub.3) δ 1.85 (p, J = 6.6 Hz, 2H), 1.95 (tt, J = 13.8, 5.7 Hz, 4H), 2.45 (t, J = 6.8 Hz, 2H), 2.50 (t, J = 5.8 Hz, 4H), 3.71 (t, J = 6.8 Hz, 2H), 4.07 (d, J = 1.6 Hz, 2H), 7.06 (m, 1H), 7.23-7.34 (m, 2H). 183 .sup.1H NMR (CDCl.sub.3) δ 2.05-2.16 (m, 2H), 2.42-2.55 (m, 2H), 2.67-2.82 (m, 1H), 3.56 (d, J = 8.0, 2H), 4.03 (s, 2H), 5.68 (m, 2H), 7.00-7.10 (m, 1H), 7.20-7.34 (m, 2H). 184 .sup.1H NMR (CDCl.sub.3) δ 0.97-1.13 (m, 1H), 1.20-1.36 (m, 1H), 1.48-1.88 (m, 6H), 1.99 (dt, J = 14.3, 4.8 Hz, 2H), 3.45 (d, J = 7.5 Hz, 1H), 3.57 (d, J = 7.5 Hz, 1H), 4.03 (s, 2H), 7.01-7.12 (m, 1H), 7.29 (m, 2H). 185 .sup.1H NMR (CDCl.sub.3) δ 1.03-1.17 (m, 1H), 1.35-1.48 (m, 2H), 1.50-1.60 (m, 2H), 1.77-1.90 (m, 2H), 1.98-2.22 (m, 2H), 3.46 (m, 2H), 4.03 (s, 1H), 4.78-4.89 (q, 1H), 7.03-7.10 (m, 1H), 7.21-7.35 (m, 2H). 186 .sup.1H NMR (CDCl.sub.3) δ 1.16 (t, J = 7.0 Hz, 6H), 3.53 (dq, J = 9.5, 7.0 Hz, 2H), 3.73 (dq, J = 9.5, 7.0 Hz, 2H), 4.87 (s, 2H), 5.19 (s, 1H), 6.92-7.06 (m, 2H), 7.33-7.43 (m, 2H). 187 .sup.1H NMR (Chloroform-d) δ 1.10 (t, J = 7.1 Hz, 6H), 3.48 (dq, J = 9.4, 7.1 Hz, 2H), 3.65 (dq, J = 9.5, 7.1 Hz, 2H), 5.11 (s, 2H), 5.17 (s, 1H), 6.97 (dt, J = 9.8, 1.4 Hz, 1H), 7.14-7.28 (m, 2H). 188 .sup.1H NMR (CDCl.sub.3) δ 1.05-1.28 (m, 4H), 1.44-1.69 (m, 4H), 1.77 (ddt, J = 13.4, 5.2, 2.7 Hz, 1H), 1.86 (d, J = 7.3 Hz, 3H), 2.19 (dd, J = 16.0, 7.1 Hz, 1H), 2.30 (dd, J = 16.0, 7.1 Hz, 1H), 5.25 (q, J = 7.3 Hz, 1H), 7.29-7.34 (m, 2H), 7.35-7.44 (m, 3H). 189 .sup.1H NMR (CDCl.sub.3) δ 1.22-1.41 (m, 2H), 1.65 (dtt, J = 33.2, 13.6, 4.0 Hz, 2H), 1.82 (ddt, J = 18.8, 12.1, 3.1 Hz, 3H), 2.03 (tdt, J = 13.3, 6.2, 2.6 Hz, 2H), 2.40 (d, J = 6.6 Hz, 2H), 4.82 (s, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.83 (dd, J = 8.3, 2.2 Hz, 1H), 8.61-8.69 (m, 1H). 190 .sup.1H NMR (CDCl.sub.3) δ 1.22-1.40 (m, 2H), 1.66 (dtt, J = 33.4, 13.7, 4.0 Hz, 2H), 1.86 (m, 3H), 2.03 (m, 2H), 4.94 (d, J = 1.3 Hz, 2H), 8.55 (s, 2H). 191 .sup.1H NMR (CDCl.sub.3) δ 1.24-1.42 (m, 2H), 1.56-1.77 (m, 2H), 1.79-1.92 (m, 3H), 1.96-2.12 (m, 2H), 2.59 (d, J = 6.6 Hz, 2H), 5.02 (s, 2H), 7.39 (d, J = 3.2 Hz, 1H), 7.73 (d, J = 3.2 Hz, 1H). 192 .sup.1H NMR (CDCl.sub.3) δ 1.19-1.36 (m, 2H), 1.52-1.70 (m, 2H), 1.80 (ddt, J = 16.7, 13.6, 3.3 Hz, 3H), 2.02 (m, 2H), 2.31 (d, J = 6.7 Hz, 2H), 2.62 (s, 3H), 4.79 (s, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H). 193 .sup.1H NMR (Methanol-d.sub.4) δ 1.25-1.42 (m, 2H), 1.59-1.90 (m, 5H), 1.90-2.09 (m, 2H), 2.63 (d, J = 6.9 Hz, 2H), 5.14 (s, 2H), 7.98 (s, 1H), 9.03 (s, 1H). 194 .sup.1H NMR (CDCl.sub.3) δ 1.24-1.40 (m, 2H), 1.55-1.90 (m, 5H), 2.04 (m, 2H), 2.50 (d, J = 6.9 Hz, 2H), 4.85 (s, 2H), 7.08 (s, 1H), 7.66 (s, 1H). 195 .sup.1H NMR (CDCl.sub.3) δ 1.23-1.37 (m, 2H), 1.57-1.76 (m, 3H), 1.82 (m, 2H), 2.05 (m, 2H), 2.18 (s, 3H), 2.41 (d, J = 6.9 Hz, 2H), 3.77 (s, 3H), 4.71 (s, 2H), 5.91 (s, 1H). 196 .sup.1H NMR (CDCl.sub.3) δ 1.29-1.44 (m, 2H), 1.73 (ddt, J = 33.1, 17.5, 4.0 Hz, 2H), 1.84-1.97 (m, 3H), 2.07 (m, 2H), 2.53 (d, J = 6.6 Hz, 2H), 2.58 (s, 3H), 4.82 (s, 2H). 197 .sup.1H NMR (CDCl.sub.3) δ 1.31-1.45 (m, 2H), 1.62-1.81 (m, 2H), 1.87-1.96 (m, 3H), 2.10 (m, 2H), 2.39 (s, 3H), 2.51 (d, J = 6.6 Hz, 2H), 4.94 (s, 2H). 198 .sup.1H NMR (CDCl.sub.3) δ 1.33-1.50 (m, 2H), 1.63-1.82 (m, 2H), 1.86-2.01 (m, 3H), 2.10 (m, 2H), 2.77 (d, J = 6.8 Hz, 2H), 5.80 (s, 2H), 6.60 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H). 199 .sup.1H NMR (CDCl.sub.3) δ 1.31-1.47 (m, 2H), 1.61-1.82 (m, 2H), 1.85-1.97 (m, 3H), 2.08 (ddt, J = 13.7, 10.2, 5.9 Hz, 2H), 2.57 (d, J = 6.4 Hz, 2H), 4.86 (s, 2H), 6.37 (s, 1H), 8.25 (s, 1H). 200 .sup.1H NMR (CDCl.sub.3) δ 1.27-1.41 (m, 2H), 1.58-1.91 (m, 5H), 2.00-2.12 (m, 2H), 2.43 (d, J = 6.6 Hz, 2H), 2.51 (s, 3H), 4.88 (s, 2H), 8.71 (s, 1H). 201 .sup.1H NMR (CDCl.sub.3) δ 1.26-1.45 (m, 2H), 1.57-1.69 (m, 1H), 1.71-1.81 (m, 2H), 1.87 (m, 2H), 2.01-2.13 (m, 2H), 2.72 (d, J = 7.0 Hz, 2H), 3.74 (s, 3H), 4.82 (s, 2H), 6.88 (d, J = 1.3 Hz, 1H), 6.95 (d, J = 1.3 Hz, 1H) 202 .sup.1H NMR (CDCl.sub.3) δ 1.17-1.32 (m, 2H), 1.58-1.76 (m, 2H), 1.81 (ddq, J = 13.3, 5.2, 2.5 Hz, 2H), 1.87-1.98 (m, 1H), 1.98-2.09 (m, 2H), 2.40 (d, J = 6.8 Hz, 2H), 4.91 (s, 2H), 7.02-7.09 (m, 2H), 7.15-7.22 (m, 2H). 203 .sup.1H NMR (CDCl.sub.3) δ 1.16-1.29 (m, 2H), 1.55-1.91 (m, 5H), 1.97-2.10 (m, 2H), 2.40 (d, J = 6.7 Hz, 2H), 5.12 (s, 2H), 7.04 (m, 1H) 7.21-7.36 (m, 2H). 204 .sup.1H NMR (CDCl.sub.3) δ 1.43 (m, 1H), 1.64-1.79 (m, 1H), 1.93-2.21 (m, 4H), 2.25-2.40 (m, 1H), 2.47 (d, J = 2.8 Hz, 2H), 4.70 (s, 2H), 6.99-7.12 (m, 2H), 7.23 (dd, J = 8.6, 5.3 Hz, 2H). 205 .sup.1H NMR (CDCl.sub.3) δ 1.43 (m, 1H), 1.62-1.78 (m, 1H), 1.91-2.18 (m, 3H), 2.22-2.44 (m, 2H), 2.48 (d, J = 6.9 Hz, 2H), 4.93 (s, 2H), 7.06 (ddd, J = 9.7, 8.3, 1.4 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.31-7.38 (m, 1H). 206 .sup.1H NMR (CDCl.sub.3) δ 0.96 (qd, J = 11.8, 3.5 Hz, 2H), 1.13-1.29 (m, 4H), 1.48-1.90 (m, 8H), 2.04-2.28 (m, 3H), 2.57 (d, J = 7.2 Hz, 2H), 2.60-2.69 (m, 1H), 3.34 (d, J = 7.4 Hz, 2H). 207 .sup.1H NMR (CDCl.sub.3) δ 1.17-1.42 (m, 2H), 1.48-1.95 (m, 7H), 2.05-2.25 (m, 5H), 2.45 (qd, J = 13.7, 8.0 Hz, 1H), 2.57 (d, J = 7.2 Hz, 2H), 2.64 (ddt, J = 10.6, 8.5, 4.4 Hz, 1H), 3.40 (d, J = 7.4 Hz, 2H). 208 .sup.1H NMR (CDCl.sub.3) δ 2.04 (s, 3H), 2.15 (s, 3H), 3.45 (s, 2H), 4.70 (s, 2H), 6.99-7.10 (m, 2H), 7.11-7.20 (m, 2H). 209 .sup.1H NMR (CDCl.sub.3) δ 2.07 (s, 3H), 2.20 (s, 3H), 3.52 (s, 2H), 4.92 (s, 2H), 7.03 (dd, J = 9.8, 8.1 Hz, 1H), 7.20-7.37 (m, 2H). 210 .sup.1H NMR (CDCl.sub.3) δ 0.93 (m, 2H), 1.08-1.30 (m, 3H), 1.70 (m, 6H), 2.20 (s, 3H), 2.34 (s, 3H), 3.30 (d, J = 7.0, 2H), 3.58 (s, 2H). 211 .sup.1H NMR (CDCl.sub.3) δ 1.24-1.39 (m, 2H), 1.58-1.88 (m, 5H), 2.13 (m, 2H), 2.21 (s, 3H), 2.35 (s, 3H), 3.38 (d, J = 7.4 Hz, 2H), 3.58 (s, 2H). 212 .sup.1H NMR (CDCl3) δ 1.95 (s, 3H), 2.04 (s, 3H), 3.53 (s, 2H), 3.58 (s, 3H), 4.59 (s, 2H), 6.94-7.08 (m, 4H). 213 .sup.1H NMR (CDCl.sub.3) δ 2.07 (brs, 6H), 3.60 (s, 2H), 3.65 (s, 3H), 4.85 (s, 2H), 7.03 (m, 1H), 7.20-7.35 (m, 2H). 214 .sup.1H NMR (CDCl.sub.3) δ 0.88 (m, 2H), 1.16 (m, 3H), 1.51-1.77 (m, 6H), 2.15 (d, J = 1.6 Hz, 6H), 3.22 (d, J = 7.2 Hz, 2H), 3.61 (s, 2H), 3.69 (s, 3H). 215 .sup.1H NMR (CDCl.sub.3) δ 1.12-1.29 (m, 2H), 1.51-1.75 (m, 5H), 2.06 (m, 2H), 2.14 (brs, 6H), 3.28 (d, J = 7.4 Hz, 2H), 3.60 (s, 2H), 3.68 (s, 3H). 216 .sup.1H NMR (CDCl.sub.3) δ 2.39 (s, 3H), 3.73 (s, 2H), 4.60 (s, 2H), 6.94-7.12 (m, 5H), 7.21-7.28 (m, 1H), 8.40 (dd, J = 5.0, 1.9 Hz, 1H). 217 .sup.1H NMR (CDCl.sub.3) δ 2.36 (s, 3H), 3.75 (s, 2H), 4.86 (d, J = 1.6 Hz, 2H), 6.83-6.98 (m, 2H), 7.03-7.21 (m, 3H), 8.27 (dt, J = 4.7, 2.3 Hz, 1H). 218 .sup.1H NMR (CDCl.sub.3) δ 0.86 (m, 2H), 1.05-1.21 (m, 2H), 1.44-1.78 (m, 7H), 2.54 (s, 3H), 3.22 (d, J = 7.1 Hz, 2H), 3.86 (s, 2H), 7.11 (dd, J = 7.7, 4.9 Hz, 1H), 7.40 (dd, J = 7.7, 1.7 Hz, 1H), 8.43 (dd, J = 5.0, 1.9 Hz, 1H). 219 .sup.1H NMR (CDCl.sub.3) δ 1.16-1.31 (m, 2H), 1.60 (m, 5H), 1.99-2.12 (m, 2H), 2.56 (s, 3H), 3.32 (d, J = 7.0 Hz, 2H), 3.88 (s, 2H), 7.16 (dd, J = 7.8, 4.9 Hz, 1H), 7.45 (dd, J = 7.8, 1.7 Hz, 1H), 8.47 (dd, J = 4.9, 1.7 Hz, 1H). 220 .sup.1H NMR (CDCl.sub.3) δ 1.89 (tt, J = 13.7, 5.7 Hz, 4H), 2.51 (t, J = 5.6 Hz, 4H), 3.35 (s, 2H), 5.11 (s, 2H), 7.05 (ddd, J = 9.8, 8.2, 1.3 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.32 (td, J = 8.1, 5.7 Hz, 1H). 221 .sup.1H NMR (CDCl.sub.3) δ 1.96 (tt, J = 12.4, 5.6 Hz, 4H), 2.57 (t, J = 5.7 Hz, 4H), 3.32 (s, 2H), 4.90 (s, 2H), 7.06 (t, J = 8.5 Hz, 2H), 7.26 (dd, J = 8.5, 5.0 Hz, 2H). 222 .sup.1H NMR (CDCl.sub.3) δ 0.98 (qd, J = 11.9, 3.3 Hz, 2H), 1.15-1.28 (m, 4H), 1.60-1.80 (m, 5H), 2.00 (tt, J = 13.7, 5.7 Hz, 4H), 2.64 (t, J = 5.7 Hz, 4H), 3.49 (d, J = 2.0 Hz, 2H), 3.53 (dd, J = 7.4, 2.0 Hz, 2H). 223 .sup.1H NMR (CDCl.sub.3) δ 1.30-1.45 (m, 2H), 1.59-1.81 (m, 4H), 2.00 m, 5H), 2.08-2.20 (m, 2H), 2.65 (t, J = 5.7 Hz, 4H), 3.49 (s, 2H), 3.61 (d, J = 7.4 Hz, 2H). 224 .sup.1H NMR (CDCl.sub.3) δ 1.74 (td, J = 6.6, 4.6 Hz, 2H), 1.88 (tt, J = 13.4, 6.3 Hz, 2H), 2.45 (t, J = 5.4 Hz, 2H), 2.66 (t, J = 11.1 Hz, 2H), 3.46 (s, 2H), 5.12 (s, 2H), 7.03 (ddd, J = 9.8, 8.2, 1.4 Hz, 1H), 7.19-7.34 (m, 2H) 225 .sup.1H NMR (CDCl.sub.3) δ 1.77 (dd, J = 6.3, 4.6 Hz, 2H), 1.91 (tt, J = 13.5, 6.5 Hz, 2H), 2.42 (t, J = 5.4 Hz, 2H), 2.64 (t, J = 11.0 Hz, 2H), 3.28 (s, 2H), 4.92 (s, 2H), 7.04 (d, J = 8.6 Hz, 1H), 7.25-7.34 (m, 2H). 226 .sup.1H NMR (CDCl.sub.3) δ 1.09 (d, J = 6.3 Hz, 3H), 1.56-1.87 (m, 2H), 1.91-2.07 (m, 2H), 2.40 (ddd, J = 12.2, 10.8, 3.2 Hz, 1H), 2.60-2.70 (m, 1H), 2.73-2.83 (m, 1H), 3.30 (d, J = 14.5 Hz, 1H), 3.89 (d, J = 14.5 Hz, 1H), 5.08 (d, J = 15.8 Hz, 1H), 5.15 (dd, J = 15.8, 1.1 Hz, 1H), 7.04 (ddd, J = 9.9, 8.1, 1.4 Hz, 1H), 7.22-7.35 (m, 2H). 227 .sup.1H NMR (CDCl.sub.3) δ 1.13 (d, J = 6.4 Hz, 3H), 2.03 (m, 3H), 2.63-2.91 (m, 2H), 3.16-3.45 (m, 1H), 3.71-3.93 (m, 1H), 4.90 (d, J = 15.5 Hz, 1H), 4.96 (d, J = 15.5 Hz, 1H), 7.07 (t, J = 8.5 Hz, 2H), 7.22-7.33 (m, 2H). 228 .sup.1H NMR (CDCl.sub.3) δ 3.10-3.17 (m, 2H), 4.08-4.12 (m, 2H), 4.17 (s, 2H), 4.82 (s, 2H), 6.58 (dd, J = 7.9, 1.9 Hz, 1H), 6.74-6.88 (m, 3H), 6.97-7.09 (m, 2H), 7.13-7.23 (m, 2H). 229 .sup.1H NMR (CDCl.sub.3) δ 3.22-3.27 (m, 2H), 4.17-4.24 (m, 2H), 4.27 (s, 2H), 5.03 (s, 2H), 6.57 (dd, J = 7.7, 1.8 Hz, 1H), 6.71-6.84 (m, 3H), 7.00 (ddd, J = 9.6, 8.1, 1.4 Hz, 1H), 7.21-7.34 (m, 2H). 230 .sup.1H NMR (CDCl.sub.3) δ 0.97 (qd, J = 11.7, 3.3 Hz, 2H), 1.13-1.30 (m, 3H), 1.58-1.84 (m, 6H), 3.26-3.33 (m, 2H), 3.47 (d, J = 7.6 Hz, 2H), 4.23-4.29 (m, 2H), 4.31 (s, 2H), 6.75-6.82 (m, 2H), 6.87 (ddt, J = 13.4, 6.5, 1.6 Hz, 2H). 231 .sup.1H NMR (CDCl.sub.3) δ 1.22-1.41 (m, 2H), 1.53-1.78 (m, 4H), 1.83-1.96(m, 1H), 2.05-2.16 (m, 2H), 3.24-3.33 (m, 2H), 3.53 (d, J = 7.5 Hz, 2H), 4.21-4.27 (m, 2H), 4.32 (s, 2H), 6.76-6.84 (m, 2H), 6.84-6.93 (m, 2H). 232 .sup.1H NMR (CDCl.sub.3) δ 2.88-2.96 (m, 4H), 3.58-3.65 (m, 4H), 4.94 (s, 2H), 6.71 (d, J = 5.1 Hz, 1H), 6.93-7.02 (m, 2H), 7.13 (d, J = 5.1 Hz, 1H), 7.24-7.32 (m, 2H). 233 .sup.1H NMR (CDCl.sub.3) δ 2.72-2.82 (m, 4H), 3.58-3.66 (m, 4H), 5.13 (s, 2H), 6.68 (d, J = 5.1 Hz, 1H), 6.94 (ddd, J = 9.7, 7.6, 2.0 Hz, 1H), 7.08 (d, J = 5.1 Hz, 1H), 7.13-7.22 (m, 2H). 234 .sup.1H NMR (CDCl.sub.3) δ 0.89-1.02 (m, 2H), 1.08-1.19 (m, 3H), 1.60-1.74 (m, 5H), 1.74-1.87 (m, 1H), 2.85-2.92 (m, 4H), 3.56 (d, J = 7.4 Hz, 2H), 3.60-3.68 (m, 4H), 6.72 (d, J = 5.1 Hz, 1H),7.11 (d, J = 5.1 Hz, 1H). 235 .sup.1H NMR (CDCl.sub.3) δ 1.17-1.42 (m, 2H), 1.46-1.65 (m, 2H), 1.66-1.75 (m, 2H), 1.90-2.13 (m, 3H), 2.86-2.93 (m, 4H), 3.60-3.64 (m, 4H), 3.66 (s, 2H), 6.72 (d, J = 5.1 Hz, 1H), 7.12 (d, J = 5.1 Hz, 1H). 236 .sup.1H NMR (CDCl.sub.3) δ 2.66 (dd, J = 6.7, 3.4 Hz, 4H), 3.20 (t, J = 5.0 Hz, 4H), 3.34 (s, 2H), 4.94 (s, 2H), 6.86-7.01 (m, 3H), 7.06 (t, J = 8.5 Hz, 2H), 7.27-7.36 (m, 4H). 237 .sup.1H NMR (CDCl.sub.3) δ 2.53-2.60 (m, 4H), 3.09 (dd, J = 6.2, 3.9 Hz, 4H), 3.37 (s, 2H), 5.15 (s, 2H), 6.83-6.93 (m, 3H), 7.03 (ddd, J = 9.8, 8.0, 1.5 Hz, 1H), 7.20-7.34 (m, 4H). 238 .sup.1H NMR (CDCl.sub.3) δ 1.00 (qd, J = 11.9, 3.3 Hz, 2H), 1.20 (ddt, J = 20.0, 16.7, 7.7 Hz, 3H), 1.63-1.80 (m, 5H), 1.82-1.86 (m, 1H), 2.64-2.72 (m, 4H), 3.16-3.23 (m, 4H), 3.50 (s, 2H), 3.57 (d, J = 7.4 Hz, 2H), 6.83-6.95 (m, 3H), 7.22-7.31 (m, 2H). 239 .sup.1H NMR (CDCl.sub.3) δ 1.33-1.45 (m, 2H), 1.66 (ddt, J = 17.6, 13.4, 4.1 Hz, 1H), 1.72-1.81 (m, 3H), 1.97-2.06 (m, 1H), 2.07-2.19 (m, 2H), 2.65-2.76 (m, 4H), 3.19 (dd, J = 6.4, 3.6 Hz, 4H), 3.50 (s, 2H), 3.65 (d, J = 7.4 Hz, 2H), 6.90 (dd, J = 15.3, 7.8 Hz, 3H), 7.27 (dd, J = 8.7, 7.2 Hz, 2H). 240 .sup.1H NMR (CDCl.sub.3) δ 1.42-1.52 (m, 2H), 1.53-1.64 (m, 4H), 2.31-2.46 (m, 4H), 3.20 (s, 2H), 4.95 (s, 2H), 7.04 (t, J = 8.6 Hz, 2H), 7.28-7.34 (m, 2H). 241 .sup.1H NMR (CDCl.sub.3) δ 1.34-1.44 (m, 2H), 1.44-1.55 (m, 4H), 2.25-2.39 (m, 4H), 3.27 (s, 2H), 5.14 (s, 2H), 7.00-7.08 (m, 1H), 7.18-7.34 (m, 2H). 242 .sup.1H NMR (CDCl.sub.3) δ 1.40 (qd, J = 12.5, 3.6 Hz, 1H), 1.51 (ddd, J = 16.1, 8.0, 3.7 Hz, 1H), 1.75 (dt, J = 13.3, 3.2 Hz, 1H), 1.82-1.91 (m, 1H), 1.99-2.11 (m, 1H), 2.32 (s, 3H), 2.60 (tt, J = 11.5, 3.6 Hz, 1H), 2.78 (dd, J = 10.6, 4.1 Hz, 2H), 3.30 (d, J = 14.2 Hz, 1H), 3.35 (d, J = 14.2 Hz, 1H), 5.13 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 15.6 Hz, 1H), 7.00-7.14 (m, 5H), 7.22-7.33 (m, 2H). 243 .sup.1H NMR (CDCl.sub.3) δ 1.45 (qd, J = 12.6, 3.9 Hz, 1H), 1.67 (td, J = 10.6, 8.8, 4.4 Hz, 1H), 1.83 (dt, J = 13.5, 3.3 Hz, 1H), 1.89-1.99 (m, 1H), 2.06-2.18 (m, 2H), 2.33 (s, 3H), 2.69 (td, J = 11.4, 3.7 Hz, 1H), 2.77-2.88 (m, 2H), 3.25 (d, J = 14.2 Hz, 1H), 3.30 (d, J = 14.2 Hz, 1H), 4.97 (s, 2H), 7.02-7.11 (m, 4H), 7.13 (d, J = 7.9 Hz, 2H), 7.29-7.35 (m, 2H). 244 .sup.1H NMR (CDCl.sub.3) δ 2.73 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 3.53 (s, 2H), 3.58 (s, 2H), 5.13 (s, 2H), 6.90-7.00 (m, 2H), 7.04-7.09 (m, 2H), 7.10-7.19 (m, 3H). 245 .sup.1H NMR (CDCl.sub.3) δ 1.22-1.38 (m, 2H), 1.42-1.62 (m, 2H), 1.65-1.75 (m, 2H), 1.89-2.10 (m, 3H), 2.84 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 6.0 Hz, 2H), 3.60-3.65 (m, 4H), 3.68 (s, 2H), 7.00-7.06 (m, 1H), 7.10-7.21 (m, 3H). 246 .sup.1H NMR (CDCl.sub.3) δ 1.64-1.81 (m, 4H), 2.40-2.52 (m, 4H), 3.44 (s, 2H), 5.13 (s, 2H), 7.02 (ddd, J = 9.7, 8.0, 1.5 Hz, 1H), 7.15-7.34 (m, 2H). 247 .sup.1H NMR (CDCl.sub.3) δ 2.22 (s, 3H), 3.79 (s, 2H), 4.96 (s, 2H), 6.96 (m, 2H,), 7.21 (m, 2H), 8.86 (s, 1H). 248 .sup.1H NMR (CDCl.sub.3) 2.24 (s, 3H), 3.76 (s, 2H), 5.07 (s, 2H), 6.91 (m, 1H), 7.13 (t, J = 8.3, 1.3 Hz, 1H), 7.37 (m, 1H), 8.86 (s, 1H). 249 .sup.1H NMR (CDCl.sub.3) 1.21-1.52 (m, 10H), 1.75 (m, 1H), 2.21 (s, 3H), 3.69 (d, J = 3.8 Hz, 2H), 3.91 (s, 2H) 8.78 (s, 1H). 250 .sup.1H NMR (CDCl.sub.3) 1.50-1.81 (m, 8H), 1.99 (m, 1H), 2.21 (s, 3H), 3.69 (d, J = 3.9 Hz, 2H), 3.85 (s, 2H), 8.69 (s, 1H). 251 .sup.1H NMR (CDCl.sub.3) 1.70-2.01 (m, 6H), 2.21 (s, 3H), 2.33 (m, 1H), 3.72 (d, J = 4.2 Hz, 2H), 3.75 (s, 2H) 8.81 (s, 1H).
Pharmacological Examples
(259) Examples of the Invention were Found to be P2X7 Inhibitors Using a Screen Quest™ Fluo-8 No Wash Calcium Assay Kit.
(260) Extracellular binding of Bz-ATP to P2X7 receptor opens the channel and allows Ca2+ influx into the cells. This Ca2+ entry was measured in HEK-293 cells stably transfected with P2X7 receptor using Screen Quest™ Fluo-8 No Wash Calcium Assay Kit (AAt Bioquest®, cat. 36316). Once inside the cell, the lipophilic blocking groups of Fluo-8 are cleaved by non-specific cell esterases, resulting in a negatively-charged fluorescent dye that stays inside cells. Its fluorescence increases upon binding to calcium. When HEK-293/P2X7 cell are stimulated with Bz-ATP, Ca.sup.2+ enters the cells and the fluorescence of Fluo-8 NW increases. The dye has an absorption spectrum compatible with excitation at 488 nm by argon laser sources and its emission wavelength is in the range of 515-575 nm.
(261) HEK-293 cells stably transfected with P2X7 receptor were seeded overnight in growth medium at 10,000 to 20,000 cell/well in 384-well plate. 24 hours later, the medium was removed and the cells were pre-loaded at RT for 1 hour with 20 μL/w of Fluo-8 NW. Then 10 μL/w of tests compounds and reference antagonist A438079 at 3×-concentration were injected with the FLIPR.sub.TETRA and the kinetic response over a period of five minutes was monitored. A second injection of 15 μL/w of 3× reference activator (Bz-ATP at EC.sub.80) was performed with the FLIPR.sub.TETRA and the signal of the emitted fluorescence was recorded for additional three minutes. All the experiment was carried out in a Low Divalent Cation Assay Buffer (0.3 mM Ca.sup.2+ and 0 mM Mg.sup.2+). The effect of the test compounds was measured as percent inhibition vs the reference antagonist and IC50 values were calculated accordingly. Here are reported the potency ranges as A, B, C and D, where A is <200 nM; B is 200 nM-104, C is 1-10 μM, D is >10 μM.
(262) TABLE-US-00013 hP2X7 rP2X7 mP2X7 Example (IC.sub.50; nM) (IC.sub.50; nM) (IC.sub.50; nM) 1 B B C 2 C D D 3 D D D 4 D D D 5 C D D 6 C C C 7 C D C 8 C D D 9 B C D 10 B C D 11 C C C 12 C B B 13 C C C 14 B C C 15 C C C 16 C C D 17 C C C 18 C C C 19 C C D 20 C C C 21 B C C 22 C C C 23 C C D 24 D D C 25 A B B 26 B A B 27 C C C 28 C D C 29 C D C 30 C C C 31 C D D 32 D D D 33 D D D 34 D D D 35 C C C 36 C D D 37 C D C 38 D D D 39 D D D 40 D D D 41 D D D 42 D D D 43 D D D 44 C C D 45 D D D 46 D D D 47 D D D 48 B B B 49 C B C 50 D D D 51 C C C 52 D D D 53 D B D 54 C D D 55 B B B 56 C C C 57 C C C 58 C C C 59 B B B 60 B C C 61 B B C 62 D D D 63 C C C 64 C D D 65 B B C 66 B B C 67 C C C 68 C D D 69 C B C 70 B C C 71 B C C 72 D D D 73 B B C 74 C C C 75 C C C 76 B B C 77 D D D 78 D D D 79 D D D 80 C C D 81 B B C 82 A A A 83 D D D 84 A A A 85 A A B 86 B B B 87 A A B 88 A A B 89 C C D 90 C C D 91 A A B 92 A A B 93 C B C 94 B B C 95 D D D 96 B B B 97 A A B 98 D C D 99 B B B 100 D D D 101 D D D 102 C C D 104 D D D 105 C C C 107 C C C 108 C C C 109 C C D 110 D C D 111 D C B 112 C B C 113 C C C 114 B A B 115 B B C 116 B B C 117 B A B 118 B B C 119 B A B 120 B A B 121 D D D 122 D C D 123 C C C 125 C B C 126 C B C 127 D D D 128 A A B 129 D C C 130 B A B 131 C C C 132 A A A 133 C C D 134 C C C 135 B D D 136 C D D 137 C C C 138 C C C 139 B B C 140 B B C 141 A A A 142 B B B 143 B B C 144 B B C 145 B B B 146 C C D 147 B B B 148 A A B 149 A A B 150 B A B 151 B B C 152 B B C 153 A A B 154 C C C 155 A B B 156 A A B 157 A A B 158 A A B 159 A A B 160 B B C 161 B B C 162 D D D 163 C C C 164 C C C 165 B A B 166 C C C 167 D C C 168 C B B 169 D C D 170 A A B 171 C B C 172 D C D 173 A A B 174 D D D 175 D D D 176 D D D 177 C C D 178 C D D 179 C D C 180 D D D 181 B C C 182 C D D 183 B B C 184 A A A 185 A A A 188 C C C 189 D D D 190 D D D 191 C B D 192 D D D 193 C B C 194 C C D 195 B B B 196 D D D 197 D D D 198 D C C 199 D C C 200 B B B 201 D C D 202 C C C 203 A A A 204 D D D 205 A A B 208 C C D 209 C D D 210 B B C 211 A B C 212 C D D 213 C D D 214 A B C 215 A B C 216 C C D 217 D D D 218 B B C 219 B C C 220 A A B 221 D C C 222 D C C 223 D D D 224 B B B 225 D C D 226 A A A 227 C B C 228 A B B 229 C C C 230 A A A 231 A A A 240 D C D 241 B A B 244 C B B
(263) Examples of the Invention were Found to be P2X7 Inhibitors Using YO-PRO®-1 Uptake Assay.
(264) YO-PRO®-1 is a fluorescent DNA-binding dye with a MW of 374 Da (Molecular Probes®, cat. Y3603). This method is based upon the presumed ability of YO-PRO®-1 to enter through the dilated or “large pore form” of P2X7 receptor and to bind to intracellular DNA whereupon it increases many fold its fluorescence intensity. The dye ha an absorption spectrum compatible with excitation at 488 nm by argon laser sources and its emission wavelength is in the range of 515-575 nm. The aim of this assay was to validate the interaction of antagonists with P2X7 receptor using an alternative readout to Ca2+-sensitive fluorescent dyes.
(265) HEK-293 cells stably transfected with P2X7 receptor were seeded overnight un growth medium at 20,000 cell/well in 384-well plate. 24 hours later, the medium was removed, the cells were washed with Low Divalent Cation Assay Buffer (0.3 mM Ca.sup.2+ and 0 mM Mg.sup.2+) and then pre-loaded with 20 μL/w of 5 μM YO-PRO®-1 dye.
(266) FLIPR.sub.TETRA fluorescence measurement immediately started. Then 10 μL/w of test compounds and reference antagonist A438079 at 3×-concentration were injected with the FLIPR.sub.TETRA and the kinetic response over a period of five minutes was monitored. A second injection of 10 μL/w of 3× Bz-ATP EC.sub.80 (30 μM) was performed with the FLIPR.sub.TETRA and the signal of the emitted fluorescence was recorded for additional 60 minutes. All the experiment was carried out with a Low Divalent Cation Assay Buffer (0.3 mM Ca.sup.2+ and 0 mM Mg.sup.2+).
(267) The effect of the test compounds was measured as percent inhibition vs the reference antagonist and IC.sub.50 values were calculated accordingly.
(268) TABLE-US-00014 Example Yo-Pro (IC.sub.50; nM) 1 581 25 115 26 329 48 340 55 50 60 366 61 293 65 318 66 456 71 461 73 670 76 168 81 619 82 30 84 3.4 85 131 86 111 87 82 88 63 91 45 92 42 94 435 96 523 97 193 99 142 114 129 115 399 116 284 117 143 118 618 119 547 120 590 128 115 130 233 132 32.00 140 181 141 31 142 467 149 66 210 184 211 171
(269) Examples of the Invention were Found to be Active on Human P2X7 Channel Assay by Automated Patch-Clamp.
(270) In order to directly monitor the block of P2X7 channel, an electrophysiological assay was developed and implemented on the QPatch16X automated electrophysiology instrument.
(271) HEK-293 cells expressing the P2X7 channels were cultured in modified EMEM.
(272) 72 hours before experiment, 5 million cells were seeded onto T225 flasks. Just before the experiment cells were washed twice, detached from the flask with trypsin-EDTA, re-suspended in the suspension solution and placed on the QPatch 16x.
(273) The compounds (20 mM in a 100% DMSO) stored at −20° C. were prepared the day of the experiment (a first dilution 1:20 in 100% DMSO to prepare a 1 mM stock solution, then a 1 microM solution in external solution+a serial dilution 1:10).
(274) The standard whole-cell voltage clamp experiments were performed at room temperature. From these experiments the multihole technology was used and the data were sampled at 2 KHz.
(275) The intracellular solution contained (mM) 135 CsF, 10 NaCl, 1 EGTA, 10 HEPES, (pH 7.2 with CsOH) whereas the extracellular contained (mM) 145 NaCl, 4 KCl, 0.5 MgCl.sub.2, 1 CaCl.sub.2, 10 HEPES, 10 Glc (pH 7.4 with NaOH).
(276) After establishment of the seal and the passage in the whole cell configuration, the cells were held at −80 mV. The P2XR7 current was evoked by applying 100 microM of BzATP alone (4 times) and then in the presence increasing concentrations of the compound under investigation (1, 10, 100 and 1000 nM).
(277) The pre-incubation periods 5 to 8 contain increasing concentrations of the compound of interest (1, 10, 100 and 1000 nM), as illustrated in FIGURE (application protocol).
FIGURE: APPLICATION PROTOCOL
(278) The maximal inward current evoked by BzATP in absence or presence of increasing concentrations of the compounds under investigation was measured and normalized. The potential agonist effect was measured as % of control and as IC50 determined fitting the dose-response curves data with the following equation:
Y=100/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope))
(279) Where:
(280) X=log of concentration
(281) Y=normalized response, 100% down to 0%, decreasing as X increases.
(282) Log IC.sub.50: same log units as X
(283) HillSlope: slope factor or HS, untiless.
(284) TABLE-US-00015 Example Q-Patch Q-Patch ± SEM 1 247.08 25.28 25 51.07 3.58 26 181.86 57.42 48 386.37 105.26 49 391.17 133.69 55 33.82 8.21 59 354.98 90.08 60 623.20 173.15 61 149.08 77.56 65 348.47 97.58 66 1496.83 760.16 71 1161.77 274.77 73 423.30 31.73 76 401.24 112.32 81 292.00 106.70 82 21.37 14.66 84 8.43 2.38 85 167.03 56.24 86 153.65 73.85 87 44.08 6.29 88 34.5 9.87 91 22.02 9.94 92 18.09 4.27 94 332.33 61.57 96 245.27 90.23 97 100.38 32.03 99 124.08 25.92 114 164.7 46.93 115 72.68 25.01 116 466.43 140.28 117 94.94 39.42 118 1086.63 394.53 119 267.77 31.16 120 161.70 14.05 128 45.22 13.20 130 94.83 29.34 132 3.36 0.32 140 39.19 7.25 141 3.04 0.16 142 153.09 123.83 149 68.55 23.70 210 149.13 24.66 211 118.98 50.23